|
Ability to inhibit the replication of HIV-1 IIIB infected C8166 cells
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phosphate derivatives of d4T as inhibitors of HIV
Year : 1993
Volume : 3
Issue : 6
First Page : 1203
Last Page : 1206
Authors : McGuigan C, Sheeka HM, Mahmood N, Hay A
|
Tested in vitro for the antiviral activity in CEM-SS cells infected with HIV-1
|
Homo sapiens
|
59.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Increase of the anti-HIV activity of D4T in human T-cell culture by the use of the sate pronucleotide approach
Year : 1995
Volume : 5
Issue : 24
First Page : 2981
Last Page : 2984
Authors : Girardet J, Perigaud C, Aubertin A, Gosselin G, Kirn A, Imbach J
|
Compound was evaluated for the inhibition of HIV replication using HIV-1 infected CEM cells.
|
Homo sapiens
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells
Year : 1996
Volume : 6
Issue : 10
First Page : 1183
Last Page : 1186
Authors : McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J
|
Compound was evaluated for the inhibition of HIV replication using HIV-2 infected CEM cells.
|
Homo sapiens
|
270.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells
Year : 1996
Volume : 6
Issue : 10
First Page : 1183
Last Page : 1186
Authors : McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J
|
Effective concentration of compound achieving 50% protection in CEM cell lines against the cytopathic effect of HIV-1
|
Homo sapiens
|
90.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of stavudine amino acid ester prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.
Year : 2004
Volume : 14
Issue : 5
First Page : 1085
Last Page : 1087
Authors : Sriram D, Yogeeswari P, Srichakravarthy N, Bal TR.
Abstract : A series of prodrugs of stavudine were synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of stavudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide, piperazine and dimethylamine acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell line and stavudine ester bearing piperazine acetic acid was found to be the most potent compound with a selective index of >15,723. Stavudine prodrug bearing ciprofloxacin and norfloxacin acetic acid showed 100% inhibition against Mycobacterium tuberculosis H(37)Rv at 6.25 microg/mL. The prodrugs also exhibited antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t(1/2) ranging from 20-240 min.
|
Activity against HIV-1 in CEM cells (in vitro)
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite.
Year : 1996
Volume : 39
Issue : 8
First Page : 1748
Last Page : 1753
Authors : McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J.
Abstract : New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.
|
Activity against HIV-2 in CEM cells (in vitro)
|
Homo sapiens
|
775.0
nM
|
|
Journal : J. Med. Chem.
Title : Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite.
Year : 1996
Volume : 39
Issue : 8
First Page : 1748
Last Page : 1753
Authors : McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J.
Abstract : New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.
|
Compound was tested for anti-HIV-1 activity in CEM/0 cell line
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Lactate cannot substitute for alanine in d4T-based anti-HIV nucleotide prodrugs--despite efficient esterase-mediated hydrolysis.
Year : 1998
Volume : 8
Issue : 21
First Page : 2949
Last Page : 2954
Authors : McGuigan C, Cahard D, Ballatore C, Siddiqui A, De Clercq E, Balzarini J.
Abstract : As part of our on-going effort to deliver masked phosphates of antiviral nucleosides inside living cells we have previously discovered that amino acid-derived phosphoramidates are particularly effective. Here we report that lactate analogues, with a simple change of bridging nitrogen for oxygen, are virtually inactive as antiviral agents and apparently do not achieve intracellular nucleoside phosphate delivery.
|
Concentration required to protect CEM/0 cells against the cytopathicity of HIV-1 by 50%
|
Human immunodeficiency virus 1
|
651.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of lipophilic phosphoramidate d4T-MP prodrugs expressing high potency against HIV in cell culture: structural determinants for in vitro activity and QSAR.
Year : 1999
Volume : 42
Issue : 20
First Page : 4122
Last Page : 4128
Authors : Siddiqui AQ, McGuigan C, Ballatore C, Zuccotto F, Gilbert IH, De Clercq E, Balzarini J.
Abstract : A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives. All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.
|
Concentration required to protect CEM/0 cells against the cytopathicity of HIV-2 by 50%
|
Human immunodeficiency virus
|
770.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of lipophilic phosphoramidate d4T-MP prodrugs expressing high potency against HIV in cell culture: structural determinants for in vitro activity and QSAR.
Year : 1999
Volume : 42
Issue : 20
First Page : 4122
Last Page : 4128
Authors : Siddiqui AQ, McGuigan C, Ballatore C, Zuccotto F, Gilbert IH, De Clercq E, Balzarini J.
Abstract : A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives. All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.
|
Effective concentration that causes 50 % inhibition of HIV-1 in CEM/0 cells, was determined.
|
Homo sapiens
|
0.4
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclic saligenyl phosphotriesters of 2,3-dideoxy-2,3-didehydrothymidine (d4T) a new pro-nucleotide approach
Year : 1997
Volume : 7
Issue : 2
First Page : 99
Last Page : 104
Authors : Meier C, Lorey M, De Clercq E, Balzarini J
|
Effective concentration that causes 50 % inhibition of HIV-2 in CEM/0 cells, was determined.
|
Homo sapiens
|
1.45
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclic saligenyl phosphotriesters of 2,3-dideoxy-2,3-didehydrothymidine (d4T) a new pro-nucleotide approach
Year : 1997
Volume : 7
Issue : 2
First Page : 99
Last Page : 104
Authors : Meier C, Lorey M, De Clercq E, Balzarini J
|
Antiviral activity was measured on HIV-1 in wild-type CEM/O cells
|
Homo sapiens
|
180.0
nM
|
|
Antiviral activity was measured on HIV-1 in wild-type CEM/O cells
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.
Year : 1998
Volume : 41
Issue : 9
First Page : 1417
Last Page : 1427
Authors : Meier C, Lorey M, De Clercq E, Balzarini J.
Abstract : The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.
|
Antiviral activity was measured on HIV-2 in wild-type CEM/O cells
|
Homo sapiens
|
260.0
nM
|
|
Antiviral activity was measured on HIV-2 in wild-type CEM/O cells
|
Homo sapiens
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.
Year : 1998
Volume : 41
Issue : 9
First Page : 1417
Last Page : 1427
Authors : Meier C, Lorey M, De Clercq E, Balzarini J.
Abstract : The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.
|
In vitro effective compound concentration required to protect CEM/O cells against the cytopathogenicity of HIV-1
|
Homo sapiens
|
651.0
nM
|
|
Journal : J. Med. Chem.
Title : The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship.
Year : 1999
Volume : 42
Issue : 3
First Page : 393
Last Page : 399
Authors : Siddiqui AQ, Ballatore C, McGuigan C, De Clercq E, Balzarini J.
Abstract : New substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble intracellular prodrugs for the free bioactive phosphate to establish relationship(s) between compound structure and in vitro antiviral activity. The majority of compounds demonstrated an elevation of in vitro potency relative to that of the parent nucleoside, and unlike d4T, all retained full activity in thymidine kinase-deficient cells. The compound bearing a p-chloro aryl group (8e) expressed nanomolar activity in vitro, a 14-fold increase in activity relative to that of the unsubstituted phosphoramidate (100-fold compared to d4T). An assay using pig liver esterase was used to establish the stability of the compounds to enzymatic degradation. While there was no apparent correlation between in vitro activity and half-life of enzymatic degradation, there was a close correlation between compound lipophilicity, determined by octanol/water partition coefficient, and in vitro potency. We suggest that substitutions made to the aryl moiety of the aryl phosphoramidate of d4T that result in enhancing lipophilicity may serve to increase the cellular uptake of the prodrug by passive diffusion, leading to the expression of antiviral potency at reduced prodrug concentrations.
|
In vitro effective compound concentration required to protect CEM/O cells against the cytopathogenicity of HIV-2
|
Homo sapiens
|
770.0
nM
|
|
Journal : J. Med. Chem.
Title : The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship.
Year : 1999
Volume : 42
Issue : 3
First Page : 393
Last Page : 399
Authors : Siddiqui AQ, Ballatore C, McGuigan C, De Clercq E, Balzarini J.
Abstract : New substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble intracellular prodrugs for the free bioactive phosphate to establish relationship(s) between compound structure and in vitro antiviral activity. The majority of compounds demonstrated an elevation of in vitro potency relative to that of the parent nucleoside, and unlike d4T, all retained full activity in thymidine kinase-deficient cells. The compound bearing a p-chloro aryl group (8e) expressed nanomolar activity in vitro, a 14-fold increase in activity relative to that of the unsubstituted phosphoramidate (100-fold compared to d4T). An assay using pig liver esterase was used to establish the stability of the compounds to enzymatic degradation. While there was no apparent correlation between in vitro activity and half-life of enzymatic degradation, there was a close correlation between compound lipophilicity, determined by octanol/water partition coefficient, and in vitro potency. We suggest that substitutions made to the aryl moiety of the aryl phosphoramidate of d4T that result in enhancing lipophilicity may serve to increase the cellular uptake of the prodrug by passive diffusion, leading to the expression of antiviral potency at reduced prodrug concentrations.
|
Effective concentration that causes 50 % inhibition of HIV-2 in CEM/TK- cells, was determined.
|
Homo sapiens
|
45.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclic saligenyl phosphotriesters of 2,3-dideoxy-2,3-didehydrothymidine (d4T) a new pro-nucleotide approach
Year : 1997
Volume : 7
Issue : 2
First Page : 99
Last Page : 104
Authors : Meier C, Lorey M, De Clercq E, Balzarini J
|
In vitro inhibition of HIV-1 replication in human T-lymphocytic cells (CEM).
|
Human immunodeficiency virus 1
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-Pronucleotides of 2',3'-dideoxyadenosine and 2', 3'-dideoxy-2',3'-didehydroadenosine: synthesis and antiviral evaluation of a highly efficient nucleotide delivery system.
Year : 1999
Volume : 42
Issue : 9
First Page : 1604
Last Page : 1614
Authors : Meier C, Knispel T, De Clercq E, Balzarini J.
Abstract : The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.
|
Antiviral activity evaluated as the ability to inhibit the replication of HIV-1 in human T-lymphocytic cells (CEM)
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-Pronucleotides of 2'-fluoro-ara- and 2'-fluoro-ribo-2',3'- dideoxyadenosine as a strategy to bypass a metabolic blockade.
Year : 1999
Volume : 42
Issue : 9
First Page : 1615
Last Page : 1624
Authors : Meier C, Knispel T, Marquez VE, Siddiqui MA, De Clercq E, Balzarini J.
Abstract : Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2', 3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.
|
In vitro inhibition of HIV-2 replication in human T-lymphocytic cells (CEM).
|
Human immunodeficiency virus 2
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-Pronucleotides of 2',3'-dideoxyadenosine and 2', 3'-dideoxy-2',3'-didehydroadenosine: synthesis and antiviral evaluation of a highly efficient nucleotide delivery system.
Year : 1999
Volume : 42
Issue : 9
First Page : 1604
Last Page : 1614
Authors : Meier C, Knispel T, De Clercq E, Balzarini J.
Abstract : The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.
|
Antiviral activity evaluated as the ability to inhibit the replication of HIV-2 in human T-lymphocytic cells (CEM)
|
Homo sapiens
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-Pronucleotides of 2'-fluoro-ara- and 2'-fluoro-ribo-2',3'- dideoxyadenosine as a strategy to bypass a metabolic blockade.
Year : 1999
Volume : 42
Issue : 9
First Page : 1615
Last Page : 1624
Authors : Meier C, Knispel T, Marquez VE, Siddiqui MA, De Clercq E, Balzarini J.
Abstract : Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2', 3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.
|
Concentration required to protect CEM cells against cytopathicity of HIV-1 by 50%
|
Homo sapiens
|
651.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhancing the aqueous solubility of d4T-based phosphoramidate prodrugs.
Year : 2000
Volume : 10
Issue : 4
First Page : 381
Last Page : 384
Authors : Siddiqui A, McGuigan C, Ballatore C, Srinivasan S, De Clercq E, Balzarini J.
Abstract : A range of polyether para-substituted phosphoramidates were synthesised and found to have substantially elevated aqueous solubilities compared to the underivatised parent prodrug. A 30-fold increase in aqueous solubility could be achieved without a substantial decrease of in vitro activity against HIV-1. Replacement of the aryl (i.e. phenolic) moiety by tyrosine led to a substantial enhancement in aqueous solubility but also to a decrease in antiviral potency. A previously unobserved trend was identified, relating increased aryl substituent steric bulk to decreased antiviral activity.
|
Concentration required to protect CEM cells against cytopathicity of HIV-2 by 50%
|
Homo sapiens
|
770.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhancing the aqueous solubility of d4T-based phosphoramidate prodrugs.
Year : 2000
Volume : 10
Issue : 4
First Page : 381
Last Page : 384
Authors : Siddiqui A, McGuigan C, Ballatore C, Srinivasan S, De Clercq E, Balzarini J.
Abstract : A range of polyether para-substituted phosphoramidates were synthesised and found to have substantially elevated aqueous solubilities compared to the underivatised parent prodrug. A 30-fold increase in aqueous solubility could be achieved without a substantial decrease of in vitro activity against HIV-1. Replacement of the aryl (i.e. phenolic) moiety by tyrosine led to a substantial enhancement in aqueous solubility but also to a decrease in antiviral potency. A previously unobserved trend was identified, relating increased aryl substituent steric bulk to decreased antiviral activity.
|
Effective concentration required to protect Human T-Lymphocyte (CEM) cells against cytopathogenicity of HIV-1 (IIIB)
|
Homo sapiens
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.
Year : 2003
Volume : 46
Issue : 15
First Page : 3292
Last Page : 3299
Authors : Choi Y, George C, Comin MJ, Barchi JJ, Kim HS, Jacobson KA, Balzarini J, Mitsuya H, Boyer PL, Hughes SH, Marquez VE.
Abstract : The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
|
Effective concentration required to protect Human T-Lymphocyte (CEM) cells against cytopathogenicity of HIV-2 (ROD)
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.
Year : 2003
Volume : 46
Issue : 15
First Page : 3292
Last Page : 3299
Authors : Choi Y, George C, Comin MJ, Barchi JJ, Kim HS, Jacobson KA, Balzarini J, Mitsuya H, Boyer PL, Hughes SH, Marquez VE.
Abstract : The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
|
Compound was tested for anti-HIV activity in TK-deficient CEM cells by p24 production assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives.
Year : 1998
Volume : 8
Issue : 22
First Page : 3121
Last Page : 3126
Authors : Venkatachalam TK, Tai HL, Vig R, Chen CL, Jan ST, Uckun FM.
Abstract : d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.
|
Concentration of the drug resulting in 50% reduction of the viral cytopathic effect against HIV-1 replication in CEM cells.
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of some modified 4-thiopyrimidine nucleosides for prevention or reversal of AIDS-associated neurological disorders.
Year : 1990
Volume : 33
Issue : 1
First Page : 258
Last Page : 263
Authors : Palomino E, Meltsner BR, Kessel D, Horwitz JP.
Abstract : Oxygen-sulfur exchange at the C-4 carbonyl of several modified pyrimidine nucleosides, including 3'-azido-3'-deoxythymidine (AZT), is described in an effort to enhance the lipophilicity and, thereby, the delivery to the central nervous system of the sulfur analogues without compromising the anti-HIV activities of the parental structures. Preparation of 3'-azido-3'-deoxy-4-thiothymidine (3) proceeded from 4-thiothymidine (1) and utilized the same methodology developed for the initial synthesis of AZT. Thiation of 2',3'-didehydro-3'-deoxythymidine (4a) and 2',3'-didehydro-2',3'-dideoxyuridine (4c) was carried out with Lawesson's reagent on the corresponding 5'-O-benzoate esters, 4b and 4d, to give 5a and 5c, respectively. The latter, on alkaline hydrolysis, gave 2',3'-didehydro-3'-deoxy-4-thiothymidine (5b) and 2',3'-didehydro-2',3'-dideoxyuridine (5d), respectively. The same series of reactions were applied to the 5'-O-benzoate esters of 2',3'-dideoxyuridine (6a) and 3'-deoxythymidine (6b) to give 2',3'-dideoxy-4-thiouridine (7d) and 3'-deoxy-4-thiothymidine (7b), respectively. Characterization of the saturated and unsaturated thionucleosides included mass spectrometric studies. Under electron impact conditions, the thiated analogues gave more intense parent ions than the corresponding oxygen precursors. The lipophilicity of thymidine and the 3'-deoxythymidine derivatives are enhanced significantly, as indicated, by increases in corresponding P values (1-octanol-0.1 M sodium phosphate) upon replacement of the 4-carbonyl oxygens by sulfur. Compounds 5b, 5d, 7b, and 7d were evaluated for their effects on HIV-induced cytopathogenicity of MT-2 and CEM cells. Only 5b and 7b were moderately active in protecting both cell lines against the cytolytic effect of HIV. The inhibitory effects of analogues 5b, 5d, 7b, and 7d on thymidine phosphorylation by rabbit thymus thymidine kinase were evaluated. Only 3 showed moderate affinity (Ki = 54 microM) for the enzyme. The generally weak anti-HIV activities of the remaining thio analogues are consistent with correspondingly low susceptibilities to thymidine kinase phosphorylation as estimated from the respective Ki values of the synthetic nucleosides. However, the phosphorylation of the 5'-monophosphate derivatives to their respective 5'-triphosphates must also be considered in connection with the weak in vitro anti-HIV effects of these thiated compounds.
|
Effective concentration that reduces HIV-induced cytopathic effect by 50% was determined by MTT assay.
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV evaluation of D4T and D4T 5'-monophosphate prodrugs.
Year : 1993
Volume : 36
Issue : 7
First Page : 826
Last Page : 830
Authors : Sergheraert C, Pierlot C, Tartar A, Henin Y, Lemaitre M.
Abstract : Several 5-monophosphate D4T derivatives and their analogues were synthesized as potential lipophilic prodrugs of D4T. Cholesteryl D4T phosphate diester and bis-5'-D4T phosphate inhibited HIV replication in CEM-Cl13 cells more efficiently than D4T itself as measured by the inhibition of cytopathic effect based on MTT assay or reverse transcriptase activity. The two compounds were devoid of toxicity on CEM-Cl13 cells at doses equal to 50 and 100 microM, respectively, which brought the selectivity index into the same range as AZT.
|
Concentration required to inhibit 50% of HIV-IIIB virus replication
|
Human immunodeficiency virus 1
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of L- and D-configuration 1,3-dioxolane 5-azacytosine and 6-azathymine nucleosides.
Year : 2000
Volume : 10
Issue : 18
First Page : 2145
Last Page : 2148
Authors : Luo MZ, Liu MC, Mozdziesz DE, Lin TS, Dutschman GE, Gullen EA, Cheng YC, Sartorelli AC.
Abstract : Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.
|
Activity against HIV-1 in MT-4 cells (in vitro)
|
Homo sapiens
|
651.0
nM
|
|
Journal : J. Med. Chem.
Title : Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite.
Year : 1996
Volume : 39
Issue : 8
First Page : 1748
Last Page : 1753
Authors : McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J.
Abstract : New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.
|
Activity against HIV-2 in MT-4 cells (in vitro)
|
Homo sapiens
|
770.0
nM
|
|
Journal : J. Med. Chem.
Title : Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite.
Year : 1996
Volume : 39
Issue : 8
First Page : 1748
Last Page : 1753
Authors : McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J.
Abstract : New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.
|
Tested in vitro for the antiviral activity in MT-4 cells infected with HIV-1
|
Homo sapiens
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Increase of the anti-HIV activity of D4T in human T-cell culture by the use of the sate pronucleotide approach
Year : 1995
Volume : 5
Issue : 24
First Page : 2981
Last Page : 2984
Authors : Girardet J, Perigaud C, Aubertin A, Gosselin G, Kirn A, Imbach J
|
Antiviral activity was measured on HIV-1 in MT-4 cells
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.
Year : 1998
Volume : 41
Issue : 9
First Page : 1417
Last Page : 1427
Authors : Meier C, Lorey M, De Clercq E, Balzarini J.
Abstract : The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.
|
Antiviral activity was measured on HIV-2 in MT-4 cells
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.
Year : 1998
Volume : 41
Issue : 9
First Page : 1417
Last Page : 1427
Authors : Meier C, Lorey M, De Clercq E, Balzarini J.
Abstract : The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.
|
Effective concentration required to protect MT-4 cells against cytopathogenicity of HIV-1 LAI
|
Homo sapiens
|
710.0
nM
|
|
Journal : J. Med. Chem.
Title : A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.
Year : 2003
Volume : 46
Issue : 15
First Page : 3292
Last Page : 3299
Authors : Choi Y, George C, Comin MJ, Barchi JJ, Kim HS, Jacobson KA, Balzarini J, Mitsuya H, Boyer PL, Hughes SH, Marquez VE.
Abstract : The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
|
Antimycobacterial activity against Mycobacterium tuberculosis strain H37Rv
|
Mycobacterium tuberculosis
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of stavudine amino acid ester prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.
Year : 2004
Volume : 14
Issue : 5
First Page : 1085
Last Page : 1087
Authors : Sriram D, Yogeeswari P, Srichakravarthy N, Bal TR.
Abstract : A series of prodrugs of stavudine were synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of stavudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide, piperazine and dimethylamine acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell line and stavudine ester bearing piperazine acetic acid was found to be the most potent compound with a selective index of >15,723. Stavudine prodrug bearing ciprofloxacin and norfloxacin acetic acid showed 100% inhibition against Mycobacterium tuberculosis H(37)Rv at 6.25 microg/mL. The prodrugs also exhibited antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t(1/2) ranging from 20-240 min.
|
Tested in vitro for the antiviral activity in PBM cells infected with HIV-1
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Increase of the anti-HIV activity of D4T in human T-cell culture by the use of the sate pronucleotide approach
Year : 1995
Volume : 5
Issue : 24
First Page : 2981
Last Page : 2984
Authors : Girardet J, Perigaud C, Aubertin A, Gosselin G, Kirn A, Imbach J
|
Antiviral activity against HIV I strain (LAV) in human peripheral blood mononuclear (PBM) cells; Range is 0.009 - 0.04
|
Homo sapiens
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells.
Year : 1989
Volume : 32
Issue : 3
First Page : 612
Last Page : 617
Authors : Chu CK, Schinazi RF, Ahn MK, Ullas GV, Gu ZP.
Abstract : The structure-activity relationships of several pyrimidine nucleosides related to 3'-azido-3'-deoxythymidine (AZT) were determined in human immunodeficiency virus type 1 (HIV-1) infected human peripheral blood mononuclear cells. These studies indicated that nucleosides with a 3'-azido group on the sugar ring exhibited the most potent antiviral activity. Substitution at C-5 with H, CH3, and C2H5 produced derivatives with the highest potency, whereas alkyl functions greater than C2, including bromovinyl substitution reduced the antiviral potency significantly. Changing the 3'-azido function to an amino or iodo group reduced the antiviral activity. Replacement of the uracil ring by cytosine or 5-methylcytosine produced analogues with high potency and low toxicity. Modification of the 5'-hydroxy group markedly reduced the antiviral activity. Similarly, various C-nucleoside analogues related to AZT and 2',3'-dideoxycytidine were inactive and nontoxic. From these systematic studies 3'-azido-2',3'-dideoxyuridine (5a), 3'-azido-5-ethyl-2',3'-dideoxyuridine (5c), and 3'-azido-2',3'-dideoxycytidine (7a) and its 5-methyl analogue (7b) were identified as potent and selective anti-HIV-1 agent in primary human lymphocytes.
|
Effective concentration required to inhibit P24 antigen production in PHA-PBM cells exposed to HIV-1 LAI
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.
Year : 2003
Volume : 46
Issue : 15
First Page : 3292
Last Page : 3299
Authors : Choi Y, George C, Comin MJ, Barchi JJ, Kim HS, Jacobson KA, Balzarini J, Mitsuya H, Boyer PL, Hughes SH, Marquez VE.
Abstract : The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
|
Effective concentration that reduces HIV-induced cytopathic effect by 50% was determined by reverse transcriptase (RT) assay.
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV evaluation of D4T and D4T 5'-monophosphate prodrugs.
Year : 1993
Volume : 36
Issue : 7
First Page : 826
Last Page : 830
Authors : Sergheraert C, Pierlot C, Tartar A, Henin Y, Lemaitre M.
Abstract : Several 5-monophosphate D4T derivatives and their analogues were synthesized as potential lipophilic prodrugs of D4T. Cholesteryl D4T phosphate diester and bis-5'-D4T phosphate inhibited HIV replication in CEM-Cl13 cells more efficiently than D4T itself as measured by the inhibition of cytopathic effect based on MTT assay or reverse transcriptase activity. The two compounds were devoid of toxicity on CEM-Cl13 cells at doses equal to 50 and 100 microM, respectively, which brought the selectivity index into the same range as AZT.
|
In vitro antiviral activity against HIV-1 Reverse transcriptase M184V mutant
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The role of 2',3'-unsaturation on the antiviral activity of anti-HIV nucleosides against 3TC-resistant mutant (M184V).
Year : 2003
Volume : 13
Issue : 12
First Page : 1993
Last Page : 1996
Authors : Choo H, Chong Y, Chu CK.
Abstract : Molecular modeling studies show that the 2',3'-double bond of the sugar moiety of various 2',3'-unsaturated nucleosides interacts with the aromatic moiety of Tyr115 of HIV-1 reverse transcriptase (RT) by hydrophobic pi-pi interaction. In 3TC-resistant mutant (M184V) RT, 2'-fluoro-2',3'-unsaturated nucleosides with a bulky 4'-substituent experience significant steric hindrance with the side chain of Val184.
|
In vitro antiviral activity against HIV-1 Reverse transcriptase wild type
|
None
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The role of 2',3'-unsaturation on the antiviral activity of anti-HIV nucleosides against 3TC-resistant mutant (M184V).
Year : 2003
Volume : 13
Issue : 12
First Page : 1993
Last Page : 1996
Authors : Choo H, Chong Y, Chu CK.
Abstract : Molecular modeling studies show that the 2',3'-double bond of the sugar moiety of various 2',3'-unsaturated nucleosides interacts with the aromatic moiety of Tyr115 of HIV-1 reverse transcriptase (RT) by hydrophobic pi-pi interaction. In 3TC-resistant mutant (M184V) RT, 2'-fluoro-2',3'-unsaturated nucleosides with a bulky 4'-substituent experience significant steric hindrance with the side chain of Val184.
|
Compound was tested for anti-HIV activity in normal peripheral blood mononuclear cells by inhibition of reverse transcriptase activity
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives.
Year : 1998
Volume : 8
Issue : 22
First Page : 3121
Last Page : 3126
Authors : Venkatachalam TK, Tai HL, Vig R, Chen CL, Jan ST, Uckun FM.
Abstract : d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.
|
Compound was tested for anti-HIV activity in normal peripheral blood mononuclear cells by p24 production assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives.
Year : 1998
Volume : 8
Issue : 22
First Page : 3121
Last Page : 3126
Authors : Venkatachalam TK, Tai HL, Vig R, Chen CL, Jan ST, Uckun FM.
Abstract : d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.
|
Effective concentration of compound to inhibit human immunodeficiency virus HIV-2 multiplication in CEM wild type cells
|
Human immunodeficiency virus 2
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach.
Year : 2005
Volume : 48
Issue : 4
First Page : 1211
Last Page : 1220
Authors : Petersen L, Jørgensen PT, Nielsen C, Hansen TH, Nielsen J, Pedersen EB.
Abstract : This paper reports the synthesis and the antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside reverse transcriptase inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside reverse transcriptase inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.
|
Effective concentration of compound to inhibit human immunodeficiency virus HIV-2 multiplication in MT-4 infected cells
|
Human immunodeficiency virus 2
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach.
Year : 2005
Volume : 48
Issue : 4
First Page : 1211
Last Page : 1220
Authors : Petersen L, Jørgensen PT, Nielsen C, Hansen TH, Nielsen J, Pedersen EB.
Abstract : This paper reports the synthesis and the antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside reverse transcriptase inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside reverse transcriptase inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.
|
Effective concentration of compound to inhibit human immunodeficiency virus HIV-1 strain N119 multiplication in CEM wild type cells
|
Human immunodeficiency virus 1
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach.
Year : 2005
Volume : 48
Issue : 4
First Page : 1211
Last Page : 1220
Authors : Petersen L, Jørgensen PT, Nielsen C, Hansen TH, Nielsen J, Pedersen EB.
Abstract : This paper reports the synthesis and the antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside reverse transcriptase inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside reverse transcriptase inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.
|
Effective concentration of compound to inhibit human immunodeficiency virus HIV-1 wild type strain IIIB multiplication in CEM wild type cells
|
Human immunodeficiency virus 1
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach.
Year : 2005
Volume : 48
Issue : 4
First Page : 1211
Last Page : 1220
Authors : Petersen L, Jørgensen PT, Nielsen C, Hansen TH, Nielsen J, Pedersen EB.
Abstract : This paper reports the synthesis and the antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside reverse transcriptase inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside reverse transcriptase inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.
|
Effective concentration of compound to inhibit human immunodeficiency virus HIV-1 wild type strain IIIB multiplication in MT-4 infected cells
|
Human immunodeficiency virus 1
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach.
Year : 2005
Volume : 48
Issue : 4
First Page : 1211
Last Page : 1220
Authors : Petersen L, Jørgensen PT, Nielsen C, Hansen TH, Nielsen J, Pedersen EB.
Abstract : This paper reports the synthesis and the antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside reverse transcriptase inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside reverse transcriptase inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.
|
Antiviral activity against HIV1 3B in MT4 cells by MTT assay
|
Human immunodeficiency virus 1
|
510.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-human immunodeficiency virus activity of 4'-branched (+/-)-4'-thiostavudines.
Year : 2006
Volume : 49
Issue : 26
First Page : 7861
Last Page : 7867
Authors : Kumamoto H, Nakai T, Haraguchi K, Nakamura KT, Tanaka H, Baba M, Cheng YC.
Abstract : Motivated by our recent finding that 4'-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4'-thio analogue, as well as other 4'-thiostavudines having a carbon substituent at the 4'-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired beta-anomer (16beta) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4'-carbomethoxy derivative (18). By using 18 as a common intermediate, 4'-carbon-substituted (CH2OH, CO2Me, CONH2, CH=CH2, CN, and C(triple bond)CH) 4'-thiostavudines were prepared. Among these six compounds, 4'-cyano (28) and 4'-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and 0.74 microM, respectively. The activity of 29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was briefly examined.
|
Antiviral activity against HIV1 in MAGI-CCR5 cells
|
Human immunodeficiency virus 1
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, in vitro antiviral evaluation, and stability studies of novel alpha-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine.
Year : 2006
Volume : 49
Issue : 26
First Page : 7799
Last Page : 7806
Authors : Barral K, Priet S, Sire J, Neyts J, Balzarini J, Canard B, Alvarez K.
Abstract : We describe here the synthesis of 9-[2-(boranophosphonomethoxy)ethyl]adenine (6a) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine (6b), the first alpha-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the alpha-phosphonate moiety. H-phosphinates 5a and 5b and alpha-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 degrees C in several media. The alpha-boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.
|
Antiviral activity against HIV1 in CEM/0 cells
|
Human immunodeficiency virus 1
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Bis-cycloSal-d4T-monophosphates: drugs that deliver two molecules of bioactive nucleotides.
Year : 2007
Volume : 50
Issue : 6
First Page : 1335
Last Page : 1346
Authors : Ducho C, Görbig U, Jessel S, Gisch N, Balzarini J, Meier C.
Abstract : Bis-cycloSal-d4T-monophosphates have been synthesized as potentially anti-HIV active "dimeric" prodrugs of 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (d4TMP). These pronucleotides display a mask-drug ratio of 1:2, a novelty in the field of pronucleotides. Both bis-cycloSal-d4TMP 6 and bis-5-methyl-cycloSal-d4TMP 7 showed increased hydrolytic stability as compared to their "monomeric" counterparts and a completely selective hydrolytic release of d4TMP. The hydrolysis pathway was investigated via 31P NMR spectroscopy. Moreover, due to the steric bulkiness, compound 6 already displayed strongly reduced inhibitor potency toward human butyrylcholinesterase (BChE), while compound 7 turned out to be devoid of any inhibitory activity against BChE. Partial separation of the diastereomeric mixture of 6 revealed strong dependence of the pronucleotides' properties on the stereochemistry at the phosphorus centers. Both 6 and 7 showed good activity against HIV-1 and HIV-2 in wild-type CEM cells in vitro. These compounds were significantly more potent than the parent nucleoside d4T 1 in HIV-2-infected TK-deficient CEM cells, indicating an efficient TK-bypass.
|
Antiviral activity against H1V2 in CEM/0 cells
|
Human immunodeficiency virus 2
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Bis-cycloSal-d4T-monophosphates: drugs that deliver two molecules of bioactive nucleotides.
Year : 2007
Volume : 50
Issue : 6
First Page : 1335
Last Page : 1346
Authors : Ducho C, Görbig U, Jessel S, Gisch N, Balzarini J, Meier C.
Abstract : Bis-cycloSal-d4T-monophosphates have been synthesized as potentially anti-HIV active "dimeric" prodrugs of 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (d4TMP). These pronucleotides display a mask-drug ratio of 1:2, a novelty in the field of pronucleotides. Both bis-cycloSal-d4TMP 6 and bis-5-methyl-cycloSal-d4TMP 7 showed increased hydrolytic stability as compared to their "monomeric" counterparts and a completely selective hydrolytic release of d4TMP. The hydrolysis pathway was investigated via 31P NMR spectroscopy. Moreover, due to the steric bulkiness, compound 6 already displayed strongly reduced inhibitor potency toward human butyrylcholinesterase (BChE), while compound 7 turned out to be devoid of any inhibitory activity against BChE. Partial separation of the diastereomeric mixture of 6 revealed strong dependence of the pronucleotides' properties on the stereochemistry at the phosphorus centers. Both 6 and 7 showed good activity against HIV-1 and HIV-2 in wild-type CEM cells in vitro. These compounds were significantly more potent than the parent nucleoside d4T 1 in HIV-2-infected TK-deficient CEM cells, indicating an efficient TK-bypass.
|
Antiviral activity against HIV1 in CEM/0 cells
|
Human immunodeficiency virus 1
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Enzymatically activated cycloSal-d4T-monophosphates: The third generation of cycloSal-pronucleotides.
Year : 2007
Volume : 50
Issue : 7
First Page : 1658
Last Page : 1667
Authors : Gisch N, Balzarini J, Meier C.
Abstract : The third generation of cycloSal-pronucleotides, 5-diacetoxymethyl-cycloSal-d4T-monophosphates (5-di-AM-cycloSal-d4TMPs), is reported as a new class of "lock-in"-modified cycloSal-pronucleotides. These compounds bear an esterase-cleavable geminal dicarboxylate (acylal) attached to the aromatic ring of the saligenyl unit. The conversion into a strong acceptor group (aldehyde) leads to a strong decrease in hydrolytic stability. As a consequence, a fast release of a nucleoside monophosphate (i.e., d4TMP) follows. The concept of this enzymatic activation is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations showed the conversion of the acylal group into a polar aldehyde by enzymatic cleavage. Besides, antiviral activities against HIV are presented.
|
Antiviral activity against HIV2 ROD in CEM/0 cells
|
Human immunodeficiency virus 2
|
630.0
nM
|
|
Journal : J. Med. Chem.
Title : Enzymatically activated cycloSal-d4T-monophosphates: The third generation of cycloSal-pronucleotides.
Year : 2007
Volume : 50
Issue : 7
First Page : 1658
Last Page : 1667
Authors : Gisch N, Balzarini J, Meier C.
Abstract : The third generation of cycloSal-pronucleotides, 5-diacetoxymethyl-cycloSal-d4T-monophosphates (5-di-AM-cycloSal-d4TMPs), is reported as a new class of "lock-in"-modified cycloSal-pronucleotides. These compounds bear an esterase-cleavable geminal dicarboxylate (acylal) attached to the aromatic ring of the saligenyl unit. The conversion into a strong acceptor group (aldehyde) leads to a strong decrease in hydrolytic stability. As a consequence, a fast release of a nucleoside monophosphate (i.e., d4TMP) follows. The concept of this enzymatic activation is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations showed the conversion of the acylal group into a polar aldehyde by enzymatic cleavage. Besides, antiviral activities against HIV are presented.
|
Inhibition of HIV1 reverse transcriptase
|
Human immunodeficiency virus 1
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs.
Year : 2007
Volume : 15
Issue : 16
First Page : 5519
Last Page : 5528
Authors : Mackman RL, Zhang L, Prasad V, Boojamra CG, Douglas J, Grant D, Hui H, Kim CU, Laflamme G, Parrish J, Stoycheva AD, Swaminathan S, Wang K, Cihlar T.
Abstract : Phosphonomethoxy nucleoside analogs of the thymine containing nucleoside reverse transcriptase inhibitors (NRTIs), 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and 2',3'-dideoxythymidine (ddT), were synthesized. The anti-HIV activity against wild-type and several major nucleoside-resistant strains of HIV-1 was evaluated together with the inhibition of wild-type HIV reverse transcriptase (RT). Phosphonomethoxy analog of d4T, 8 (d4TP), demonstrated antiviral activity with an EC(50) value of 26 microM, whereas, phosphonomethoxy analogs of ddT, 7 (ddTP), and AZT, 6 (AZTP), were both inactive at concentrations up to 200 microM. Bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs improved the anti-HIV activity of 7 and 8 by >150-fold and 29-fold, respectively, allowing for antiviral resistance to be determined. The K65R RT mutant virus was more resistant to the bisPOC prodrugs of 7 and 8 than bisPOC PMPA (tenofovir DF) 1. However, bisPOC prodrug of 7 demonstrated superior resistance toward the RT virus containing multiple thymidine analog mutations (6TAMs) indicating that new phosphonate nucleoside analogs may be suitable for targeting clinically relevant nucleoside resistant HIV-1 strains.
|
Inhibition of HIV1-induced cytopathogenicity in CEM/0 cells
|
Human immunodeficiency virus 1
|
650.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives.
Year : 2007
Volume : 17
Issue : 13
First Page : 3666
Last Page : 3669
Authors : Mehellou Y, McGuigan C, Brancale A, Balzarini J.
Abstract : We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.
|
Inhibition of HIV2-induced cytopathogenicity in CEM/0 cells
|
Human immunodeficiency virus 2
|
770.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives.
Year : 2007
Volume : 17
Issue : 13
First Page : 3666
Last Page : 3669
Authors : Mehellou Y, McGuigan C, Brancale A, Balzarini J.
Abstract : We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.
|
Antiviral activity against HIV1 in wild type human CEM cells assessed as virus-induced cytopathic effect after 4 to 5 days by microscopy
|
Human immunodeficiency virus 1
|
560.0
nM
|
|
Journal : J. Med. Chem.
Title : Doubly loaded cycloSaligenyl-pronucleotides - 5,5'-Bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates).
Year : 2009
Volume : 52
Issue : 11
First Page : 3464
Last Page : 3473
Authors : Gisch N, Balzarini J, Meier C.
Abstract : Recently, we reported on 3,3'-bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates) (3,3'-bis-(cycloSal-d4TMPs) 4) as the first pronucleotides with a mask-to-drug ratio of 1:2 that is still a novelty in the field of pronucleotides. Here, we report on a new set of compounds of these unique type of cycloSaligenyl prodrugs 5 that bear a biaryl axis at the 5-position of the cycloSal residue. All compounds 5 showed pronounced in vitro activity against HIV-1 and HIV-2 in wild-type CEM cell cultures and better retained their antiviral activities in thymidine kinase-deficient CEM cells than the compound 4 series. Moreover, compound 5b is the first bis-(cycloSal-d4TMP) that even showed complete retention of antiviral activity in TK-deficient CEM cells. The complex hydrolysis behavior of 5 was investigated, and the proposed hydrolysis mechanism was proven by means of (31)P NMR spectroscopy and HPLC analysis.
|
Antiviral activity against HIV2 in wild type human CEM cells assessed as virus-induced cytopathic effect after 4 to 5 days by microscopy
|
Human immunodeficiency virus 2
|
790.0
nM
|
|
Journal : J. Med. Chem.
Title : Doubly loaded cycloSaligenyl-pronucleotides - 5,5'-Bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates).
Year : 2009
Volume : 52
Issue : 11
First Page : 3464
Last Page : 3473
Authors : Gisch N, Balzarini J, Meier C.
Abstract : Recently, we reported on 3,3'-bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates) (3,3'-bis-(cycloSal-d4TMPs) 4) as the first pronucleotides with a mask-to-drug ratio of 1:2 that is still a novelty in the field of pronucleotides. Here, we report on a new set of compounds of these unique type of cycloSaligenyl prodrugs 5 that bear a biaryl axis at the 5-position of the cycloSal residue. All compounds 5 showed pronounced in vitro activity against HIV-1 and HIV-2 in wild-type CEM cell cultures and better retained their antiviral activities in thymidine kinase-deficient CEM cells than the compound 4 series. Moreover, compound 5b is the first bis-(cycloSal-d4TMP) that even showed complete retention of antiviral activity in TK-deficient CEM cells. The complex hydrolysis behavior of 5 was investigated, and the proposed hydrolysis mechanism was proven by means of (31)P NMR spectroscopy and HPLC analysis.
|
Antiviral activity against 0.1 MOI HIV1 3B infected in human TZM-b1 cells assessed as inhibition of viral replication at 6 uM after 24 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
50.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Intracellular metabolism and persistence of the anti-human immunodeficiency virus activity of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel thymidine analog.
Year : 2007
Volume : 51
Issue : 11
First Page : 3870
Last Page : 3879
Authors : Paintsil E, Dutschman GE, Hu R, Grill SP, Lam W, Baba M, Tanaka H, Cheng YC.
Abstract : The therapeutic benefits of current antiretroviral therapy are limited by the evolution of drug-resistant virus and long-term toxicity. Novel antiretroviral compounds with activity against drug-resistant viruses are needed. 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a novel thymidine analog, has potent anti-human immunodeficiency virus (HIV) activity, maintains considerable activity against multidrug-resistant HIV strains, and is less inhibitory to mitochondrial DNA synthesis in cell culture than its progenitor stavudine (D4T). We investigated the intracellular metabolism and anti-HIV activity of 4'-Ed4T. The profile of 4'-Ed4T metabolites was qualitatively similar to that for zidovudine (AZT), with the monophosphate metabolite as the major metabolite, in contrast to that for D4T, with relatively poor formation of total metabolites. The first phosphorylation step for 4'-Ed4T in cells was more efficient than that for D4T but less than that for AZT. The amount of 4'-Ed4T triphosphate (4'-Ed4TTP) was higher than that of AZTTP at 24 h in culture. There was a dose-dependent accumulation of 4'-Ed4T diphosphate and 4'-Ed4TTP on up-regulation of thymidylate kinase and 3-phosphoglycerate kinase expression in Tet-On RKO cells, respectively. The anti-HIV activity of 4'-Ed4T in cells persisted even after 48 h of drug removal from culture in comparison with AZT, D4T, and nevirapine (NVP). The order of increasing persistence of anti-HIV activity of these compounds after drug removal was 4'-Ed4T > D4T > AZT > NVP. In conclusion, with the persistence of 4'-Ed4TTP and persistent anti-HIV activity in cells, we anticipate less frequent dosing and fewer patient compliance issues than for D4T. 4'-Ed4T is a promising antiviral candidate for HIV type 1 chemotherapy.
|
Antiviral activity against 0.1 MOI HIV1 3B infected in human TZM-b1 cells assessed as inhibition of viral replication at 2 uM after 24 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
50.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Intracellular metabolism and persistence of the anti-human immunodeficiency virus activity of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel thymidine analog.
Year : 2007
Volume : 51
Issue : 11
First Page : 3870
Last Page : 3879
Authors : Paintsil E, Dutschman GE, Hu R, Grill SP, Lam W, Baba M, Tanaka H, Cheng YC.
Abstract : The therapeutic benefits of current antiretroviral therapy are limited by the evolution of drug-resistant virus and long-term toxicity. Novel antiretroviral compounds with activity against drug-resistant viruses are needed. 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a novel thymidine analog, has potent anti-human immunodeficiency virus (HIV) activity, maintains considerable activity against multidrug-resistant HIV strains, and is less inhibitory to mitochondrial DNA synthesis in cell culture than its progenitor stavudine (D4T). We investigated the intracellular metabolism and anti-HIV activity of 4'-Ed4T. The profile of 4'-Ed4T metabolites was qualitatively similar to that for zidovudine (AZT), with the monophosphate metabolite as the major metabolite, in contrast to that for D4T, with relatively poor formation of total metabolites. The first phosphorylation step for 4'-Ed4T in cells was more efficient than that for D4T but less than that for AZT. The amount of 4'-Ed4T triphosphate (4'-Ed4TTP) was higher than that of AZTTP at 24 h in culture. There was a dose-dependent accumulation of 4'-Ed4T diphosphate and 4'-Ed4TTP on up-regulation of thymidylate kinase and 3-phosphoglycerate kinase expression in Tet-On RKO cells, respectively. The anti-HIV activity of 4'-Ed4T in cells persisted even after 48 h of drug removal from culture in comparison with AZT, D4T, and nevirapine (NVP). The order of increasing persistence of anti-HIV activity of these compounds after drug removal was 4'-Ed4T > D4T > AZT > NVP. In conclusion, with the persistence of 4'-Ed4TTP and persistent anti-HIV activity in cells, we anticipate less frequent dosing and fewer patient compliance issues than for D4T. 4'-Ed4T is a promising antiviral candidate for HIV type 1 chemotherapy.
|
Antiviral activity against HIV1 in human wild type CEM/0 cellss
|
Human immunodeficiency virus 1
|
860.0
nM
|
|
Journal : J. Med. Chem.
Title : Studies on enzyme-cleavable dialkoxymethyl-cyclosaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates.
Year : 2008
Volume : 51
Issue : 21
First Page : 6752
Last Page : 6760
Authors : Gisch N, Balzarini J, Meier C.
Abstract : Recently we reported on conceptually new enzymatically activated cycloSal-pronucleotides. Now, we developed this concept further with new compounds of this type. The basic idea is fast intracellular cleavage of a functionalized group at the cycloSal residue that results in a rapid delivery of the nucleotide and thus an intracellular enrichment of the nucleotide. The introduction of a higher alkylated acylal group, the di- iso-butyryloxymethyl group, to the aromatic ring led to the expected higher stability of these prodrugs against enzymatic cleavage but also entailed surprisingly a decrease in hydrolysis stabilities and solubility problems. For some compounds, a separation of the two diastereomeric forms ( R P or S P) was achieved. By X-ray structure analysis, the absolute configuration at the P-atom was assigned. For all separated diastereomers the ( S P) form showed better antiviral activity than the ( R P) form.
|
Antiviral activity against HIV1 in human CEM cells
|
Human immunodeficiency virus 1
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Intracellular trapping of cycloSal-pronucleotides: modification of prodrugs with amino acid esters.
Year : 2008
Volume : 51
Issue : 20
First Page : 6592
Last Page : 6598
Authors : Jessen HJ, Balzarini J, Meier C.
Abstract : A new class of d4TMP- cycloSal-pronucleotides bearing enzymatically cleavable amino acid esters is reported. These compounds are designed to trap the pronucleotide inside the cell by a fast conversion of a nonpolar ester group into a charged carboxylate. This should prevent efficient diffusion equilibrium across the cell membrane to the extracellular environment, leading to an intracellular accumulation of the compounds. This initial conversion is followed by a slow release of the nucleoside monophosphate (i.e., d4TMP). The concept is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations revealed a high sensitivity of some amino acid ester modifications to conversion by cellular extracts, resulting in the fast release of a charged intermediate, whereas no cleavage of the modification is found in phosphate buffer. In addition, antiviral activities against HIV are presented.
|
Antiviral activity against HIV2 ROD in human CEM cells
|
Human immunodeficiency virus 2
|
630.0
nM
|
|
Journal : J. Med. Chem.
Title : Intracellular trapping of cycloSal-pronucleotides: modification of prodrugs with amino acid esters.
Year : 2008
Volume : 51
Issue : 20
First Page : 6592
Last Page : 6598
Authors : Jessen HJ, Balzarini J, Meier C.
Abstract : A new class of d4TMP- cycloSal-pronucleotides bearing enzymatically cleavable amino acid esters is reported. These compounds are designed to trap the pronucleotide inside the cell by a fast conversion of a nonpolar ester group into a charged carboxylate. This should prevent efficient diffusion equilibrium across the cell membrane to the extracellular environment, leading to an intracellular accumulation of the compounds. This initial conversion is followed by a slow release of the nucleoside monophosphate (i.e., d4TMP). The concept is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations revealed a high sensitivity of some amino acid ester modifications to conversion by cellular extracts, resulting in the fast release of a charged intermediate, whereas no cleavage of the modification is found in phosphate buffer. In addition, antiviral activities against HIV are presented.
|
Antiviral activity against HIV1 3B in human H9 cells assessed as inhibition of virus-induced cytopathic effect by formazan-based conventional colorimetric technique
|
Human immunodeficiency virus 1
|
60.0
nM
|
|
Journal : J. Nat. Prod.
Title : Natural product-based anti-HIV drug discovery and development facilitated by the NCI developmental therapeutics program.
Year : 2001
Volume : 64
Issue : 2
First Page : 265
Last Page : 277
Authors : Yang SS, Cragg GM, Newman DJ, Bader JP.
Abstract : During the decade 1987-1996, the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) provided infrastructure support for both intramural and extramural anti-HIV (human immunodeficiency virus) drug discovery research and development. This retrospective review describes some of the anti-HIV lead discovery and development that took place under DTP auspices or which was substantially facilitated by resources made available through the DTP. Examples highlighted include leads identified through the initial screening of pure natural product derived compounds and those derived from bioassay-guided fractionation of crude natural product extracts, and these are classified according to the mechanism of action targeting the critical steps within the replication cycle of HIV.
|
Antiviral activity against HIV1 RF in human H9 cells assessed as inhibition of virus-induced cytopathic effect by formazan-based conventional colorimetric technique
|
Human immunodeficiency virus 1
|
60.0
nM
|
|
Journal : J. Nat. Prod.
Title : Natural product-based anti-HIV drug discovery and development facilitated by the NCI developmental therapeutics program.
Year : 2001
Volume : 64
Issue : 2
First Page : 265
Last Page : 277
Authors : Yang SS, Cragg GM, Newman DJ, Bader JP.
Abstract : During the decade 1987-1996, the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) provided infrastructure support for both intramural and extramural anti-HIV (human immunodeficiency virus) drug discovery research and development. This retrospective review describes some of the anti-HIV lead discovery and development that took place under DTP auspices or which was substantially facilitated by resources made available through the DTP. Examples highlighted include leads identified through the initial screening of pure natural product derived compounds and those derived from bioassay-guided fractionation of crude natural product extracts, and these are classified according to the mechanism of action targeting the critical steps within the replication cycle of HIV.
|
Antiviral activity against HIV1 replication in human wild type CEM/0 cells assessed as virus-induced cytopathic effect
|
Human immunodeficiency virus 1
|
850.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-(1-Acetoxyvinyl)-cycloSaligenyl-2',3'-dideoxy-2',3'- didehydrothymidine monophosphates, a second type of new, enzymatically activated cycloSaligenyl pronucleotides.
Year : 2008
Volume : 51
Issue : 24
First Page : 8115
Last Page : 8123
Authors : Gisch N, Pertenbreiter F, Balzarini J, Meier C.
Abstract : In our attempt to further develop the cycloSal pronucleotide concept, we report on 5-(1-acetoxyvinyl)-cycloSal-d4TMPs as a new type of enzyme-activated pronucleotides. These compounds were converted into 5-acetyl-cycloSal-d4TMPs by (carboxy)esterase cleavage inside the cells. The enzymatic reaction led to the formation of a strong electron-withdrawing substituent that strongly accelerates the chemical hydrolysis of the cycloSal nucleotide to give d4TMP. For some cycloSal-d4TMPs a separation into the diastereomers was achieved. The absolute configuration was assigned by correlation of circular dichroism spectra with similar compounds. Most of the compounds showed complete retention of antiviral activity in TK-deficient CEM/TK(-) cells, which proves the TK-bypass potential of this approach. Interestingly, (S(P))-isomers of cycloSal phosphate triesters showed better antiviral activity in HIV-2-infected thymidine-kinase deficient CEM/TK(-) cells than their (R(P))-counterparts.
|
Antiviral activity against HIV1 reverse transcriptase Y181C mutant infected in human MT2 cells assessed as inhibition of viral replication by MTT assay
|
Human immunodeficiency virus 1
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives.
Year : 2010
Volume : 20
Issue : 8
First Page : 2485
Last Page : 2488
Authors : Leung CS, Zeevaart JG, Domaoal RA, Bollini M, Thakur VV, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with the assistance of free energy perturbation (FEP) calculations to predict relative free energies of binding. Extension of azole-containing inhibitors into an 'eastern' channel between Phe227 and Pro236 has led to the discovery of potent and structurally novel derivatives.
|
Antiviral activity against HIV1 reverse transcriptase K103N/Y181C double mutant infected in human MT2 cells assessed as inhibition of viral replication by MTT assay
|
Human immunodeficiency virus 1
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives.
Year : 2010
Volume : 20
Issue : 8
First Page : 2485
Last Page : 2488
Authors : Leung CS, Zeevaart JG, Domaoal RA, Bollini M, Thakur VV, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with the assistance of free energy perturbation (FEP) calculations to predict relative free energies of binding. Extension of azole-containing inhibitors into an 'eastern' channel between Phe227 and Pro236 has led to the discovery of potent and structurally novel derivatives.
|
Antiviral activity against HIV1 3B infected in human CEM/0 cells assessed as inhibition of virus-induced cytopathicity after 4 to 5 days
|
Human immunodeficiency virus 1
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : Diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3'-deoxy-2',3'-didehydrothymidine monophosphate.
Year : 2010
Volume : 53
Issue : 21
First Page : 7675
Last Page : 7681
Authors : Roman CA, Balzarini J, Meier C.
Abstract : The first diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3'-deoxy-2',3'-didehydrothymidine monophosphate (d4TMP) is reported. In our approach, (S)-4-isopropylthiazolidine-2-thione 1 was used as a chiral auxiliary to introduce the stereochemistry at the phosphorus atom. In the last step of the developed reaction sequence, the nucleoside analogue d4T was introduced to a stereochemically pure phosphordiamidate which led to the formation of the almost diastereomerically pure phosphoramidate prodrugs 8a-d (≥95% de). As expected, the individually prepared diastereomers of the phosphoramidate prodrugs showed significant differences in the antiviral activity. Moreover, the difference was strongly dependent on the aryl substituent attached to the phosphoramidate moiety.
|
Antiviral activity against HIV2 ROD infected in human CEM/0 cells assessed as inhibition of virus-induced cytopathicity after 4 to 5 days
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : Diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3'-deoxy-2',3'-didehydrothymidine monophosphate.
Year : 2010
Volume : 53
Issue : 21
First Page : 7675
Last Page : 7681
Authors : Roman CA, Balzarini J, Meier C.
Abstract : The first diastereoselective synthesis of aryloxy phosphoramidate prodrugs of 3'-deoxy-2',3'-didehydrothymidine monophosphate (d4TMP) is reported. In our approach, (S)-4-isopropylthiazolidine-2-thione 1 was used as a chiral auxiliary to introduce the stereochemistry at the phosphorus atom. In the last step of the developed reaction sequence, the nucleoside analogue d4T was introduced to a stereochemically pure phosphordiamidate which led to the formation of the almost diastereomerically pure phosphoramidate prodrugs 8a-d (≥95% de). As expected, the individually prepared diastereomers of the phosphoramidate prodrugs showed significant differences in the antiviral activity. Moreover, the difference was strongly dependent on the aryl substituent attached to the phosphoramidate moiety.
|
Antiviral activity against HIV1 isolate 056 expressing wild type reverse transcriptase gene by phenosense assay
|
Human immunodeficiency virus 1
|
510.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 057 expressing wild type reverse transcriptase gene by phenosense assay
|
Human immunodeficiency virus 1
|
480.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 066 harboring reverse transcriptase 184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
460.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 070 harboring reverse transcriptase 65R/S68G mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
770.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 071 harboring reverse transcriptase 65R/S68N/184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
590.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 153 harboring reverse transcriptase L74V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
600.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 157 harboring reverse transcriptase L74V/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
420.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 166 harboring reverse transcriptase L74V mutant gene obtained as site-directed mutant of NL4-3 by phenosense assay
|
Human immunodeficiency virus 1
|
630.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 174 harboring reverse transcriptase M184V mutant gene obtained as site-directed mutant of NL4-3 by phenosense assay
|
Human immunodeficiency virus 1
|
400.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 180 harboring reverse transcriptase K65R mutant gene obtained as site-directed mutant of NL4-3 by phenosense assay
|
Human immunodeficiency virus 1
|
830.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 185 harboring reverse transcriptase T215Y mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
830.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 188 harboring reverse transcriptase T215Y/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
650.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 192 harboring reverse transcriptase M41L/T215Y mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
840.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 194 harboring reverse transcriptase M41L/T215Y/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
860.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 203 harboring reverse transcriptase M41L/L210W/T215Y/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
880.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 206 harboring reverse transcriptase D67N/K70R mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
780.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 211 harboring reverse transcriptase D67N/K70R/T215F/K219E/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
790.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 212 harboring reverse transcriptase L210W/T215Y mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
940.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 215 harboring reverse transcriptase D67N/K70E mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
560.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 217 harboring reverse transcriptase D67N/K70E/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
420.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 220 harboring reverse transcriptase K70E/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
390.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 infected in human PBMC assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anti-human immunodeficiency virus activity, cross-resistance, cytotoxicity, and intracellular pharmacology of the 3'-azido-2',3'-dideoxypurine nucleosides.
Year : 2009
Volume : 53
Issue : 9
First Page : 3715
Last Page : 3719
Authors : Sluis-Cremer N, Koontz D, Bassit L, Hernandez-Santiago BI, Detorio M, Rapp KL, Amblard F, Bondada L, Grier J, Coats SJ, Schinazi RF, Mellors JW.
Abstract : Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3'-azido-2',3'-dideoxypurine nucleosides (ADPNs) 3'-azido-2',3'-dideoxyadenosine (3'-azido-ddA) and 3'-azido-2',3'-dideoxyguanosine (3'-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC50s] range from 0.19 to 2.1 microM for 3'-azido-ddG and from 0.36 to 10 microM for 3'-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3'-azido-ddA and 3'-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC50 change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC50 change of <3.5-fold). In addition, 3'-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3'-azido-ddG is efficiently phosphorylated to 3'-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection.
|
Antiviral activity against HIV-1 infected in wild type CEM cells assessed as inhibition of virus-induced cytopathicity after 4 days
|
Human immunodeficiency virus 1
|
780.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereoselective synthesis and antiviral activity of methyl-substituted cycloSal-pronucleotides.
Year : 2012
Volume : 55
Issue : 16
First Page : 7245
Last Page : 7252
Authors : Rios Morales EH, Balzarini J, Meier C.
Abstract : Methyl-substituted cycloSal-pronucleotides of d4TMP were synthesized with high diastereoselectivities in satisfying chemical yields. The individual diastereomers were tested against HIV-1 and HIV-2 infected wild-type CEM/0 and HIV-2 infected thymidine kinase deficient CEM cells. All diastereomers tested showed significant antiviral activity in CEM/0 and strong activity in CEM/TK(-) cell cultures. The antiviral activities were strongly dependent on the chirality at the phosphate group and the position of the methyl-group(s) in the cycloSal moiety. In CEM/TK(-) cell cultures the difference in antiviral potency was found to be 7- to 20-fold. The stability of each diastereomer was studied in aqueous phosphate buffer and in CEM/0 cell extracts. Large differences in the half-lives were found. A comparison of the relative lipophilicity of the methyl-substituted cycloSal triesters was performed based on the retention times obtained by reversed phase HPLC. The results obtained clearly confirm the importance of a diastereoselective synthesis of cycloSal-pronucleotides.
|
Antiviral activity against HIV2 ROD infected in human CEM cells assessed as virus-induced giant cell formation after 4 days by microscopic analysis
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
580.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides.
Year : 2013
Volume : 70
First Page : 326
Last Page : 340
Authors : McGuigan C, Bourdin C, Derudas M, Hamon N, Hinsinger K, Kandil S, Madela K, Meneghesso S, Pertusati F, Serpi M, Slusarczyk M, Chamberlain S, Kolykhalov A, Vernachio J, Vanpouille C, Introini A, Margolis L, Balzarini J.
Abstract : We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-Alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by (31)P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields.
|
Antiviral activity against HIV1 3B infected in human CEM cells assessed as virus-induced giant cell formation after 4 days by microscopic analysis
|
Human immunodeficiency virus 1
|
390.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides.
Year : 2013
Volume : 70
First Page : 326
Last Page : 340
Authors : McGuigan C, Bourdin C, Derudas M, Hamon N, Hinsinger K, Kandil S, Madela K, Meneghesso S, Pertusati F, Serpi M, Slusarczyk M, Chamberlain S, Kolykhalov A, Vernachio J, Vanpouille C, Introini A, Margolis L, Balzarini J.
Abstract : We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-Alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by (31)P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields.
|
Antiviral activity against HIV-2 ROD infected in human MT4 cells
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hydroxy fatty acids for the delivery of dideoxynucleosides as anti-HIV agents.
Year : 2014
Volume : 24
Issue : 3
First Page : 817
Last Page : 820
Authors : Gangadhara KL, Lescrinier E, Pannecouque C, Herdewijn P.
Abstract : A series of α- and β-carboxylated phospholipid prodrugs of dideoxy nucleosides have been synthesized and evaluated against HIV. An increase in biological effect with a factor of 500 has only been observed for the adenine nucleoside, which suggests that this prodrug approach is base specific.
|
Antiviral activity against HIV-1 3B infected in human MT4 cells
|
Human immunodeficiency virus 1
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hydroxy fatty acids for the delivery of dideoxynucleosides as anti-HIV agents.
Year : 2014
Volume : 24
Issue : 3
First Page : 817
Last Page : 820
Authors : Gangadhara KL, Lescrinier E, Pannecouque C, Herdewijn P.
Abstract : A series of α- and β-carboxylated phospholipid prodrugs of dideoxy nucleosides have been synthesized and evaluated against HIV. An increase in biological effect with a factor of 500 has only been observed for the adenine nucleoside, which suggests that this prodrug approach is base specific.
|
Antiviral activity against HIV1 3B infected in human CEM/0 cells assessed as reduction in virus-induced giant cell formation incubated for 4 to 5 days
|
Human immunodeficiency virus 1
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides.
Year : 2015
Volume : 58
Issue : 15
First Page : 6114
Last Page : 6130
Authors : Weinschenk L, Schols D, Balzarini J, Meier C.
Abstract : Nonsymmetric DiPPro-nucleotides are described as nucleoside diphosphate (NDP) delivery systems. The concept is to attach different bis(acyloxybenzyl) moieties at the β-phosphate moiety of a NDP. DiPPro compounds bearing two alkanoylbenzyl residues and DiPPro compounds bearing an alkanoylbenzyl or a benzoylbenzyl group as bioreversible prodrug moieties were studied. Compounds bearing short chain alkanoyl esters led to a fast hydrolysis by chemical or enzymatic means. The ester group in the second prodrug group comprised a long lipophilic aliphatic or an aromatic residue. The lipophilicity of this group enabled the prodrug to penetrate the cell membrane. The introduction of two different groups allowed a controlled stepwise removal of the prodrug moieties to achieve a highly selective delivery of the NDP in CEM cell extracts. The compounds were highly active against HIV even in thymidine kinase-deficient CEM cells. Thus, the compounds, although charged at the α-phosphate group, were taken up by the cells and released NDPs.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
17.22
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
4.38
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
14.08
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
16.08
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
24.61
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.99
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
0.51
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
6.09
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antiviral activity against wild type HIV-1 3B infected in human MT4 cells
|
Human immunodeficiency virus 1
|
400.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity.
Year : 2019
Volume : 29
Issue : 24
First Page : 126721
Last Page : 126721
Authors : Kandil S, Pannecouque C, Chapman FM, Westwell AD, McGuigan C.
Abstract : Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge. Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF5) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC50 = 30 nM, HIV-1) and (IC50 = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK-) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both 31P and 19F NMR is presented.
|
Antiviral activity against HIV-2 ROD infected in human MT4 cells
|
Human immunodeficiency virus type 1
|
450.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity.
Year : 2019
Volume : 29
Issue : 24
First Page : 126721
Last Page : 126721
Authors : Kandil S, Pannecouque C, Chapman FM, Westwell AD, McGuigan C.
Abstract : Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge. Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF5) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC50 = 30 nM, HIV-1) and (IC50 = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK-) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both 31P and 19F NMR is presented.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.34
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
0.8086
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antiviral activity against HIV1 3B infected in human CEM/0 cells assessed as inhibition of viral-induced giant cell formation incubated for 4 to 5 days by microscopy
|
Human immunodeficiency virus 1
|
430.0
nM
|
|
Journal : J Med Chem
Title : Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues.
Year : 2020
Volume : 63
Issue : 13
First Page : 6991
Last Page : 7007
Authors : Jia X, Schols D, Meier C.
Abstract : The antiviral efficacy of many nucleoside analogues is strongly dependent on their intracellular activation by host cellular kinases to yield ultimately the bioactive nucleoside analogue triphosphates (NTP). The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. We developed a nucleoside triphosphate (NTP) delivery system (the Tri<i>PPP</i>ro approach), in which the γ-phosphate is covalently modified by two different biodegradable masking units, one is the acyloxybenzyl (AB) moiety and the other is the alkoxycarbonyloxybenzyl (ACB) group. Such compounds formed NTPs with high selectivity by an enzyme-triggered mechanism in human T-lymphocyte CEM cell extracts loosing first the AB moiety, followed by the ACB group. This enables the bypass of all steps of the intracellular phosphorylation. This approach was applied here to convert some modestly active or even inactive nucleoside analogues into powerful biologically active metabolites. Potent antiviral activity profiles were obtained depending on the lipophilicity of the Tri<i>PPP</i>ro-NTP prodrugs against HIV-1 and HIV-2 replication in cultures of infected wild-type CD4<sup>+</sup> CEM T-cells and more importantly in thymidine kinase-deficient CD4<sup>+</sup> T-cells (CEM/TK<sup>-</sup>). This Tri<i>PPP</i>ro strategy offers high potential for future antiviral and antitumoral chemotherapies.
|
Antiviral activity against HIV2 ROD infected in human CEM/0 cells assessed as inhibition of viral-induced giant cell formation incubated for 4 to 5 days by microscopy
|
Human immunodeficiency virus type 1
|
310.0
nM
|
|
Journal : J Med Chem
Title : Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues.
Year : 2020
Volume : 63
Issue : 13
First Page : 6991
Last Page : 7007
Authors : Jia X, Schols D, Meier C.
Abstract : The antiviral efficacy of many nucleoside analogues is strongly dependent on their intracellular activation by host cellular kinases to yield ultimately the bioactive nucleoside analogue triphosphates (NTP). The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. We developed a nucleoside triphosphate (NTP) delivery system (the Tri<i>PPP</i>ro approach), in which the γ-phosphate is covalently modified by two different biodegradable masking units, one is the acyloxybenzyl (AB) moiety and the other is the alkoxycarbonyloxybenzyl (ACB) group. Such compounds formed NTPs with high selectivity by an enzyme-triggered mechanism in human T-lymphocyte CEM cell extracts loosing first the AB moiety, followed by the ACB group. This enables the bypass of all steps of the intracellular phosphorylation. This approach was applied here to convert some modestly active or even inactive nucleoside analogues into powerful biologically active metabolites. Potent antiviral activity profiles were obtained depending on the lipophilicity of the Tri<i>PPP</i>ro-NTP prodrugs against HIV-1 and HIV-2 replication in cultures of infected wild-type CD4<sup>+</sup> CEM T-cells and more importantly in thymidine kinase-deficient CD4<sup>+</sup> T-cells (CEM/TK<sup>-</sup>). This Tri<i>PPP</i>ro strategy offers high potential for future antiviral and antitumoral chemotherapies.
|
Antiviral activity against HIV1 3B infected in human CEM/0 cells assessed as inhibition of virus-induced giant cell formation measured after 4 to 5 days by microscopic analysis
|
Human immunodeficiency virus 1
|
430.0
nM
|
|
Journal : J Med Chem
Title : Anti-HIV-Active Nucleoside Triphosphate Prodrugs.
Year : 2020
Volume : 63
Issue : 11
First Page : 6003
Last Page : 6027
Authors : Jia X, Schols D, Meier C.
Abstract : We disclose a study on nucleoside triphosphate (NTP) analogues in which the γ-phosphate is covalently modified by two different biodegradable masking units and d4T as nucleoside analogue that enable the delivery of d4TTP with high selectivity in phosphate buffer (pH 7.3) and by enzyme-triggered reactions in human CD4+ T-lymphocyte CEM cell extracts. This allows the bypass of all steps normally needed in the intracellular phosphorylation. These TriPPPro-nucleotides comprising an acyloxybenzyl (AB; ester) or an alkoxycarbonyloxybenzyl (ACB; carbonate) in combination with an ACB moiety are described as NTP delivery systems. The introduction of these two different groups led to the selective formation of γ-(ACB)-d4TTPs by chemical hydrolysis and in particular by cell extract enzymes. γ-(AB)-d4TTPs are faster cleaved than γ-(ACB)-d4TTPs. In antiviral assays, the compounds are highly active against HIV-1 and HIV-2 in wild-type CEM/O cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK-).
|
Antiviral activity against HIV2 ROD infected in human CEM/0 cells assessed as inhibition of virus-induced giant cell formation measured after 4 to 5 days by microscopic analysis
|
Human immunodeficiency virus type 1
|
310.0
nM
|
|
Journal : J Med Chem
Title : Anti-HIV-Active Nucleoside Triphosphate Prodrugs.
Year : 2020
Volume : 63
Issue : 11
First Page : 6003
Last Page : 6027
Authors : Jia X, Schols D, Meier C.
Abstract : We disclose a study on nucleoside triphosphate (NTP) analogues in which the γ-phosphate is covalently modified by two different biodegradable masking units and d4T as nucleoside analogue that enable the delivery of d4TTP with high selectivity in phosphate buffer (pH 7.3) and by enzyme-triggered reactions in human CD4+ T-lymphocyte CEM cell extracts. This allows the bypass of all steps normally needed in the intracellular phosphorylation. These TriPPPro-nucleotides comprising an acyloxybenzyl (AB; ester) or an alkoxycarbonyloxybenzyl (ACB; carbonate) in combination with an ACB moiety are described as NTP delivery systems. The introduction of these two different groups led to the selective formation of γ-(ACB)-d4TTPs by chemical hydrolysis and in particular by cell extract enzymes. γ-(AB)-d4TTPs are faster cleaved than γ-(ACB)-d4TTPs. In antiviral assays, the compounds are highly active against HIV-1 and HIV-2 in wild-type CEM/O cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK-).
|
Antiviral activity against HIV1 3B infected in human CEM/0 cells assessed as inhibition of virus-induced syncytia cell formation measured after 4 to 5 days by microscopic analysis
|
Human immunodeficiency virus 1
|
430.0
nM
|
|
Journal : J Med Chem
Title : γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals.
Year : 2020
Volume : 63
Issue : 22
First Page : 13745
Last Page : 13761
Authors : Nack T,Dinis de Oliveira T,Weber S,Schols D,Balzarini J,Meier C
Abstract : The antiviral activity of nucleoside reverse transcriptase inhibitors is often hampered by insufficient phosphorylation. Nucleoside triphosphate analogues are presented, in which the γ-phosphate was covalently modified by a non-bioreversible, lipophilic 4-alkylketobenzyl moiety. Interestingly, primer extension assays using human immunodeficiency virus reverse transcriptase (HIV-RT) and three DNA-polymerases showed a high selectivity of these γ-modified nucleoside triphosphates to act as substrates for HIV-RT, while they proved to be nonsubstrates for DNA-polymerases α, β, and γ. In contrast to d4TTP, the γ-modified d4TTPs showed a high resistance toward dephosphorylation in cell extracts. A series of acyloxybenzyl-prodrugs of these γ-ketobenzyl nucleoside triphosphates was prepared. The aim was the intracellular delivery of a stable γ-modified nucleoside triphosphate to increase the selectivity of such compounds to act in infected versus noninfected cells. Delivery of γ-ketobenzyl-d4TTPs was proven in T-lymphocyte cell extracts. The prodrugs were potent inhibitors of HIV-1/2 in cultures of infected CEM/0 cells and more importantly in thymidine kinase-deficient CD4 T-cells.
|
Antiviral activity against HIV2 ROD infected in human CEM/0 cells assessed as inhibition of virus-induced syncytia cell formation measured after 4 to 5 days by microscopic analysis
|
Human immunodeficiency virus type 1
|
220.0
nM
|
|
Journal : J Med Chem
Title : γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals.
Year : 2020
Volume : 63
Issue : 22
First Page : 13745
Last Page : 13761
Authors : Nack T,Dinis de Oliveira T,Weber S,Schols D,Balzarini J,Meier C
Abstract : The antiviral activity of nucleoside reverse transcriptase inhibitors is often hampered by insufficient phosphorylation. Nucleoside triphosphate analogues are presented, in which the γ-phosphate was covalently modified by a non-bioreversible, lipophilic 4-alkylketobenzyl moiety. Interestingly, primer extension assays using human immunodeficiency virus reverse transcriptase (HIV-RT) and three DNA-polymerases showed a high selectivity of these γ-modified nucleoside triphosphates to act as substrates for HIV-RT, while they proved to be nonsubstrates for DNA-polymerases α, β, and γ. In contrast to d4TTP, the γ-modified d4TTPs showed a high resistance toward dephosphorylation in cell extracts. A series of acyloxybenzyl-prodrugs of these γ-ketobenzyl nucleoside triphosphates was prepared. The aim was the intracellular delivery of a stable γ-modified nucleoside triphosphate to increase the selectivity of such compounds to act in infected versus noninfected cells. Delivery of γ-ketobenzyl-d4TTPs was proven in T-lymphocyte cell extracts. The prodrugs were potent inhibitors of HIV-1/2 in cultures of infected CEM/0 cells and more importantly in thymidine kinase-deficient CD4 T-cells.
|
Antiviral activity against HIV1 3B infected in human CEM/0 CD4+ T cells assessed as reduction in virus-induced cytopathogenicity by measuring syncytia cell formation incubated for 4 to 5 days by microscopy
|
Human immunodeficiency virus 1
|
430.0
nM
|
|
Journal : J Med Chem
Title : Membrane Permeable, Bioreversibly Modified Prodrugs of Nucleoside Diphosphate-γ-Phosphonates.
Year : 2020
Volume : 63
Issue : 20
First Page : 11990
Last Page : 12007
Authors : Jia X,Weber S,Schols D,Meier C
Abstract : Nucleoside reverse transcriptase inhibitors (NRTIs) are widely used as antiviral and anticancer agents, although they require intracellular phosphorylation into their antivirally active form, the triphosphorylated nucleoside analogue metabolites. We report on the synthesis and characterization of a new class of nucleoside triphosphate analogues comprising a C-alkyl-phosphonate moiety replacing the γ-phosphate. These compounds were converted into bioreversibly modified lipophilic prodrugs at the γ-phosphonate by the attachment of an acyloxybenzyl (ester) or an alkoxycarbonyloxybenzyl (carbonate) group. Such compounds formed γ-C-(alkyl)-nucleoside triphosphate analogues with high selectivity because of an enzyme-triggered delivery mechanism. The latter compounds were very stable in CD4 T-lymphocyte (CEM cell) extracts, and they were substrates for HIV-reverse transcriptase without being substrates for DNA-polymerases α, β, and γ. In antiviral assays, the excellent antiviral activity of the prodrugs that was found in CEM/0 cells was completely kept in CEM/TK cells. The activity was improved by 3 logs as compared to the parent nucleoside d4T.
|
Antiviral activity against HIV2 ROD infected in human CEM/0 CD4+ T cells assessed as reduction in virus-induced cytopathogenicity by measuring syncytia cell formation incubated for 4 to 5 days by microscopy
|
Human immunodeficiency virus type 1
|
310.0
nM
|
|
Journal : J Med Chem
Title : Membrane Permeable, Bioreversibly Modified Prodrugs of Nucleoside Diphosphate-γ-Phosphonates.
Year : 2020
Volume : 63
Issue : 20
First Page : 11990
Last Page : 12007
Authors : Jia X,Weber S,Schols D,Meier C
Abstract : Nucleoside reverse transcriptase inhibitors (NRTIs) are widely used as antiviral and anticancer agents, although they require intracellular phosphorylation into their antivirally active form, the triphosphorylated nucleoside analogue metabolites. We report on the synthesis and characterization of a new class of nucleoside triphosphate analogues comprising a C-alkyl-phosphonate moiety replacing the γ-phosphate. These compounds were converted into bioreversibly modified lipophilic prodrugs at the γ-phosphonate by the attachment of an acyloxybenzyl (ester) or an alkoxycarbonyloxybenzyl (carbonate) group. Such compounds formed γ-C-(alkyl)-nucleoside triphosphate analogues with high selectivity because of an enzyme-triggered delivery mechanism. The latter compounds were very stable in CD4 T-lymphocyte (CEM cell) extracts, and they were substrates for HIV-reverse transcriptase without being substrates for DNA-polymerases α, β, and γ. In antiviral assays, the excellent antiviral activity of the prodrugs that was found in CEM/0 cells was completely kept in CEM/TK cells. The activity was improved by 3 logs as compared to the parent nucleoside d4T.
