|
Ability to inhibit the episomal HBV-DNA in 2.2.15 cells.
|
Homo sapiens
|
2.1
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-DNA viral activities in vitro of certain 2,4-disubstituted-7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)pyrrolo[2,3-d d pyrimidine nucleosides.
Year : 1995
Volume : 38
Issue : 20
First Page : 3957
Last Page : 3966
Authors : Bhattacharya BK, Ojwang JO, Rando RF, Huffman JH, Revankar GR.
Abstract : Several novel 2,4-disubstituted-7-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl)pyrrolo[2,3-d]pyrimidines have been synthesized and evaluated for their anti-human cytomegalovirus (HCMV), anti-hepatitis B virus (HBV), and anti-herpes simplex virus (HSV) activities in vitro. These nucleosides were prepared starting from 2-amino-4-chloro-7-(2-deoxy-2-fluoro- 3,5-di-O-benzoyl-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (3), which in turn was synthesized by direct glycosylation of the sodium salt of 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (1) with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-D-arabinofuranosyl bromide (2). Displacement of the 4-chloro group of 3 with OH, NH2, NHOH, SH, and SeH nucleophiles furnished the corresponding nucleosides 6-8, 12, and 14, respectively. The 3'-deoxygenation of 2-amino-4-chloro-7- (2-deoxy-2-fluoro-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (4) and subsequent amination gave 2,4-diamino-2',3'-dideoxy derivative 19. Catalytic hydrogenation of 3 followed by debenzoylation afforded 2-aminopyrrolo[2,3-d]pyrimidine nucleoside 23. Among the compounds evaluated for their ability to inhibit the growth of HCMV (strain AD169) in MRC-5 cells using a plaque reduction assay, only 7 was significantly active in vitro with a 50% inhibitory concentration (IC50) of 3.7 micrograms/mL (TI > 125), whereas the IC50 value of ganciclovir (DHPG) was 3.2 micrograms/mL. Strain D16 of HCMV was more resistant to 7 (IC50 11 micrograms/mL) than the AD169 strain. When 7 was tested in combination with DHPG, the resultant anti-HCMV activity was found to be moderately synergistic with no evidence of antagonism. Nucleoside 7 also reduced episomal HBV replication in human hepatoblastoma 2.2.15 cells with an IC50 of 0.7 micrograms/mL (TI > 143). Development of cells harboring HBV which had become resistant to the drug was not observed with 7. Compound 7 also exhibited significant activity against herpes simplex virus types 1 and 2 (IC50 of 4.1 and 6.3 micrograms/mL, respectively) in Vero cells.
|
Antiviral activity against HIV-1 (RF strain) in C8166 cells
|
Homo sapiens
|
125.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiviral activity of monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1).
Year : 1990
Volume : 33
Issue : 8
First Page : 2137
Last Page : 2145
Authors : Martin JA, Bushnell DJ, Duncan IB, Dunsdon SJ, Hall MJ, Machin PJ, Merrett JH, Parkes KE, Roberts NA, Thomas GJ.
Abstract : A range of 2'-fluoro and 2',3'-difluoro analogues of pyrimidine deoxyribonucleosides have been synthesized and evaluated against human immunodeficiency virus (HIV-1) in a human lymphoblastoid cell line. Among these compounds, 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12), 2',3'-didehydro-2',3'-dideoxy-2'-fluorocytidine (35), 1-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)cytosine (41), and 3'-deoxy-2',3'-didehydro-2'-fluorothymidine (45) were found to have significant antiviral activity, with IC50 values of 0.65, 10, 10, and 100 microM, respectively. The structure-activity relationships are discussed.
|
Concentration of compound required to inhibit the synthesis of mitochondrial DNA (mt DNA) in human CCRF-CEM T-lymphoblastic leukemia cells
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 2',3'-dideoxy-L-pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV).
Year : 1994
Volume : 37
Issue : 6
First Page : 798
Last Page : 803
Authors : Lin TS, Luo MZ, Liu MC, Pai SB, Dutschman GE, Cheng YC.
Abstract : Various 2',3'-dideoxy-L-cytidine,2',3'-dideoxy-L-uridine, and 3'-deoxy-L-thymidine analogues have been synthesized and evaluated in vitro as potential anti-HIV and anti-HBV agents. Coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (1) with silylated derivatives of 5-fluorocytosine, cytosine, 5-fluorouracil, uracil, and thymine in the presence of ethylaluminum dichloride gave the corresponding nucleosides 2, 3, 4, 5, 10, 11, 12, 16, 17, and 18 as a mixture of alpha- and beta-anomers, which were then deblocked to yield the corresponding 2',3'-dideoxy-L-5-fluorocytidine derivatives, 6 and 7, 2',3'-dideoxy-L-cytidine derivatives, 8 and 9, 2',3'-dideoxy-beta-L-fluorouridine (13), 2',3'-dideoxy-beta-L-uridine (14), and 3'-deoxy-L-thymidine derivatives, 15 and 19. Among these 2',3'-dideoxy-L-nucleoside analogues, 2',3'-dideoxy-beta-L-5-fluorocytidine (6, beta-L-FddC) was found to be the most active against HIV-1, which is approximately 3 and 4 times more active against HIV-1 in vitro than 2',3'-dideoxy-beta-D-cytidine (ddC) and 2',3'-dideoxy-beta-D-5-fluorocytidine (beta-D-FddC) with ED50 values of 0.5, 1.5, and 2 microM, respectively. The dose-limiting toxicity of ddC is severe neuropathy which may be caused by the inhibition of the synthesis of mitochondrial DNA. ddC has an IC50 value of 0.022 microM against host mitochondrial DNA synthesis. Conversely, the IC50 values for beta-L-FddC and beta-L-ddC are > 100 microM; therefore, neuropathy may not present itself to be a problem with beta-L-FddC and beta-L-ddC as chemotherapeutic agents. In addition, beta-L-FddC and 2',3'-dideoxy-beta-L-cytidine (8, beta-L-ddC) demonstrated equally potent activity against HBV in vitro by having the same ED50 value of 0.01 microM. Both beta-L-FddC and beta-L-ddC, which have an "unnatural" L-configuration in the sugar moiety, are approximately 1000 and 280 times more potent, respectively, against HBV than the D-configuration beta-D-FddC and ddC which have an ED50 values of 10 and 2.8 microM. In view of the potent antiviral activity of beta-L-FddC against both HIV-1 and HBV and potent antiviral activity of beta-L-ddC against HBV in vitro, their low cytotoxicity, and especially the negligible inhibitory effect on host mitochondrial DNA synthesis, beta-L-FddC and beta-L-ddC merit further development as potential anti-HIV and anti-HBV agents.
|
Effective concentration required to achieve 50% inhibition of HIV-1 LAI replication in human T4 lymphoblastoid CEM-SS cells.
|
Human immunodeficiency virus 1
|
31.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase.
Year : 2000
Volume : 43
Issue : 10
First Page : 1927
Last Page : 1939
Authors : Pontikis R, Dollé V, Guillaumel J, Dechaux E, Note R, Nguyen CH, Legraverend M, Bisagni E, Aubertin AM, Grierson DS, Monneret C.
Abstract : To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. In marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC(50) = 0.45 microM) against HIV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was observed for these bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respective sites. Interestingly, however, the results indicate that the AZT-HEPT conjugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the former compounds interact preferentially with the hydrophobic pocket in RT, whereas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.
|
Concentration required to achieve 50% protection of CEM-SS cells against the cytopathic effect of HIV-1.
|
Human immunodeficiency virus 1
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV-1 activity of a series of 1-alkoxy-5-alkyl-6-(arylthio)uracils.
Year : 1997
Volume : 40
Issue : 15
First Page : 2363
Last Page : 2373
Authors : Kim DK, Gam J, Kim YW, Lim J, Kim HT, Kim KH.
Abstract : A series of 1-alkoxy-5-alkyl-6-(arylthio)uracils was synthesized and tested for their ability to inhibit HIV-1 replication. Treatment of 2-alkyl-3,3-bis(methylthio)acryloyl chlorides (5a-e) with AgOCN in benzene followed by reaction of the resulting isocyanates 6a-e with an appropriate alkoxyamine gave N-alkoxy-N'-((2-alkyl-3,3-bis(methylthio)acryloyl)ureas (10a-z) in good to excellent yields. Cyclization of 10a-z in AcOH containing a catalytic amount of p-TsOH produced 1-alkoxy-5-alkyl-6-(methylthio)uracils (11a-z). Oxidation of 11a-z with 3-chloroperoxybenzoic acid in CH2Cl2 resulted in high yields of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils (12a-x and 12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y), which were subsequently reacted with an appropriate arenethiol in ethanolic NaOH solution to afford 1-alkoxy-5-alkyl-6-(arylthio)uracils (14-49). Substitution at the 3- and 5-positions of the C-6-(phenylthio) ring by two methyl groups significantly increased its original anti-HIV-1 activity (EC50: 6-((3,5-dimethylphenyl)thio)-5-isopropyl-1-propoxyuracil (18), 0.064 microM; 6-((3,5-dimethylphenyl)thio)-1-(3-hydroxypropoxy)-5-isopropyluracil++ + (23), 0.19 microM). Among the various alkoxy substituents at the N-1, the propoxy group was the most beneficial for improving the anti-HIV-1 activity. The 1-propoxy derivative 18 proved to be the most potent inhibitor of HIV-1 replication, followed by the 1-(3-hydroxypropoxy) derivative 23. Introduction of an isopropyl group at C-5 of the uracil base also remarkably enhanced the activity. When compound 18 was incubated with a rat liver homogenate preparation, no metabolite was observed, thus confirming the metabolic stability of the N-O bond in these 1-alkoxyuracils.
|
Anti-HIV activity against HIV-I RFII strain in CEM cell line
|
Homo sapiens
|
189.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers.
Year : 1996
Volume : 39
Issue : 6
First Page : 1303
Last Page : 1313
Authors : Flavin MT, Rizzo JD, Khilevich A, Kucherenko A, Sheinkman AK, Vilaychack V, Lin L, Chen W, Greenwood EM, Pengsuparp T, Pezzuto JM, Hughes SH, Flavin TM, Cibulski M, Boulanger WA, Shone RL, Xu ZQ.
Abstract : The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
|
Compound was evaluated for the antiviral activity against HIV-1 strain IIIB in CEM-SS cells
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI.
Year : 1998
Volume : 8
Issue : 16
First Page : 2179
Last Page : 2184
Authors : Xu ZQ, Buckheit RW, Stup TL, Flavin MT, Khilevich A, Rizzo JD, Lin L, Zembower DE.
Abstract : The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2), were evaluated for in vitro antiviral activities against HIV and simian immunodeficiency virus (SIV). The compounds were determined to be inhibitors of HIV-1 reverse transcriptase (RT) and exhibited activity against a variety of viruses selected for resistance to other HIV-1 nonnucleoside RT inhibitors. They are the first reported calanolide analogues capable of inhibiting SIV.
|
Compound was evaluated for the antiviral activity against HIV-1 strain RF in CEM-SS cells
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI.
Year : 1998
Volume : 8
Issue : 16
First Page : 2179
Last Page : 2184
Authors : Xu ZQ, Buckheit RW, Stup TL, Flavin MT, Khilevich A, Rizzo JD, Lin L, Zembower DE.
Abstract : The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2), were evaluated for in vitro antiviral activities against HIV and simian immunodeficiency virus (SIV). The compounds were determined to be inhibitors of HIV-1 reverse transcriptase (RT) and exhibited activity against a variety of viruses selected for resistance to other HIV-1 nonnucleoside RT inhibitors. They are the first reported calanolide analogues capable of inhibiting SIV.
|
Compound was evaluated for the antiviral activity against HIV-1 strain SK1 in CEM-SS cells
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI.
Year : 1998
Volume : 8
Issue : 16
First Page : 2179
Last Page : 2184
Authors : Xu ZQ, Buckheit RW, Stup TL, Flavin MT, Khilevich A, Rizzo JD, Lin L, Zembower DE.
Abstract : The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2), were evaluated for in vitro antiviral activities against HIV and simian immunodeficiency virus (SIV). The compounds were determined to be inhibitors of HIV-1 reverse transcriptase (RT) and exhibited activity against a variety of viruses selected for resistance to other HIV-1 nonnucleoside RT inhibitors. They are the first reported calanolide analogues capable of inhibiting SIV.
|
Compound was evaluated for the antiviral activity against SIV delta in CEM-SS cells
|
Homo sapiens
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI.
Year : 1998
Volume : 8
Issue : 16
First Page : 2179
Last Page : 2184
Authors : Xu ZQ, Buckheit RW, Stup TL, Flavin MT, Khilevich A, Rizzo JD, Lin L, Zembower DE.
Abstract : The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2), were evaluated for in vitro antiviral activities against HIV and simian immunodeficiency virus (SIV). The compounds were determined to be inhibitors of HIV-1 reverse transcriptase (RT) and exhibited activity against a variety of viruses selected for resistance to other HIV-1 nonnucleoside RT inhibitors. They are the first reported calanolide analogues capable of inhibiting SIV.
|
Effect on HIV-induced cytopathogenesis in CEM cells.
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemistry and anti-HIV properties of 2'-fluoro-2',3'-dideoxyarabinofuranosylpyrimidines.
Year : 1992
Volume : 35
Issue : 12
First Page : 2195
Last Page : 2201
Authors : Siddiqui MA, Driscoll JS, Marquez VE, Roth JS, Shirasaka T, Mitsuya H, Barchi JJ, Kelley JA.
Abstract : The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'-dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compounds is a potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after greater than 24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.
|
Compound was tested for its inhibitory activity against HIV replication in CEM cells.
|
Homo sapiens
|
0.05
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV activity of 4'-thio-2',3'-dideoxynucleosides.
Year : 1992
Volume : 35
Issue : 3
First Page : 533
Last Page : 538
Authors : Secrist JA, Riggs RM, Tiwari KN, Montgomery JA.
Abstract : A series of 2',3'-dideoxy-4'-thionucleoside analogues of purines and pyrimidines, including 4'-thioddI (17), 4'-thioddC (27), and 4'-thioAZT (34), were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). A stereospecific synthesis of the 2,3-dideoxy-4-thioribofuranosyl carbohydrate precursor 11 starting with L-glutamic acid is described. 2',3'-Dideoxy-4'-thiocytidine (27) displayed significant, but modest activity in vitro against human immunodeficiency virus.
|
Inhibitory concentration against mitochondrial DNA synthesis CEM cells
|
Homo sapiens
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : (Z)- and (E)-2-((hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New nucleoside analogues with a broad-spectrum antiviral activity.
Year : 1998
Volume : 41
Issue : 1
First Page : 10
Last Page : 23
Authors : Qiu YL, Ksebati MB, Ptak RG, Fan BY, Breitenbach JM, Lin JS, Cheng YC, Kern ER, Drach JC, Zemlicka J.
Abstract : New nucleoside analogues 14-17 based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, which was benzoylated to give N6,N6-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with ethyl diazoacetate catalyzed by Rh2(OAc)4 were futile. By contrast, 2,3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters 26 + 27. More convenient one-pot alkylation-elimination of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 afforded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 32. The Z-isomers were always predominant in these mixtures (Z/E approximately 2/1). Reduction of 26 + 27 and 31 + 32 with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols 14 + 16 and 33 + 34. The latter were resolved directly by chromatography. Compounds 14 + 16 were converted to N6-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 with HCO2H led to guanine analogues 15 and 17. The 1H NMR spectra of the Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, 1H NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues 14, 15, and 33 were the most effective agents against HCMV (IC50 1-2.1, 0.04-2.1, and 0.8-5.6 microM), MCMV (IC50 2.1, 0.3, and 0.3 microM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 microM) and Daudi cells (IC50 3.2, 5.6, and 1.2 microM). Adenine analogue 14 was active against HBV (IC50 2 microM), VZV (IC50 2.5 microM), and HHV-6 (IC50 14 microM). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reactive than Z-isomer 14. The deamination of 14 effectively stopped at 50% conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.
|
Inhibition of HIV-1 replication in H9 lymphocytic cells.
|
Human immunodeficiency virus 1
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-HIV activity of quassinoids
Year : 1996
Volume : 6
Issue : 6
First Page : 701
Last Page : 706
Authors : Okano M, Fukamiya N, Tagahara K, Cosentino M, Lee TT, Morris-Natschke S, Lee K
|
Effective concentration required to achieve 50% protection of MT-4 cells against the cytopathic effect of HIV-1 (HTLV-IIIB).
|
Human immunodeficiency virus
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : A new class of HIV-1-specific 6-substituted acyclouridine derivatives: synthesis and anti-HIV-1 activity of 5- or 6-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
Year : 1991
Volume : 34
Issue : 1
First Page : 349
Last Page : 357
Authors : Tanaka H, Baba M, Hayakawa H, Sakamaki T, Miyasaka T, Ubasawa M, Takashima H, Sekiya K, Nitta I, Shigeta S.
Abstract : A series of novel acyclouridine derivatives substituted at both the C-5 and C-6 positions were synthesized for the purpose of improving the activity of a recently reported HIV-1-specific lead, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). Preparation of C-6 substituted derivatives was carried out based on the following three methods: (1) LDA (lithium diisopropylamide) lithiation of a thymine derivative (4) and subsequent reaction with electrophiles, (2) an addition-elimination reaction of HEPT or its 6-(phenylsulfinyl) derivative (10), or (3) palladium-catalyzed cross-coupling between a 6-iodo derivative (16) and terminal alkynes. Following the methods, 21 C-6 substituted analogues were synthesized. Among these, 6-(cyclohexylthio) (8), 6-phenoxy (13), and 6-benzyl (27) derivatives showed anti-HIV-1 (HTLV-IIIB) activity with EC50 values of 8.2, 85, and 23 microM, respectively. Preparation of C-5 substituted derivatives was based on either LTMP (lithium 2,2,6,6-tetramethylpiperidide) lithiation of 6-(phenylthio)uracil derivative 37 or the above mentioned palladium-catalyzed cross-coupling of a 5-iodo-6-(phenylthio)uracil derivative (38). Following these methods, 11 C-5 substituted analogues were synthesized. Some 5-substituted derivatives (5-I, 44; 5-CH = CPh2, 49; 5-CH = CHPh (Z), 54; and 5-CH = CH2, 55) were more active than HEPT, but their selectivity indices (SI = CC50/EC50) were lower than that of HEPT. Compound 8 was also evaluated against another HIV-1 strain (HTLV-IIIRF) and HIV-2 strains (LAV-2ROD and LAV-2EHO). Only HTLV-IIIRF was as sensitive as HTLV-IIIB.
|
Concentration required to protect 50% of HIV-1 infected MT-4 cells against viral cytopathicity.
|
Human immunodeficiency virus 1
|
910.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential prodrug derivatives of 2',3'-didehydro-2',3'-dideoxynucleosides. Preparations and antiviral activities.
Year : 1992
Volume : 35
Issue : 15
First Page : 2728
Last Page : 2735
Authors : Mullah KB, Rao TS, Balzarini J, De Clercq E, Bentrude WG.
Abstract : The preparations and antiviral activities of a series (4-17) of potential prodrug forms of the antivirals 2',3'-didehydro-2',3'-dideoxyadenosine (D4A) and 2',3'-didehydro-2',3'-dideoxycytosine (D4C) are reported. The 5'-phenyl- and 5'-methylphosphonates (4, 6, 8, and 10) and their phosphonothionate congeners (5, 7, 9, and 11), with the exception of 10, were inactive in vitro against HIV-1 and HIV-2. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. This strongly suggests that the diesters are hydrolyzed to the nucleosides D4A and D4C and/or their 5'-monophosphates. The facile hydrolysis of 12 and 13 to these products was demonstrated in a medium containing 10% fetal calf serum. The molecules can serve as ready prodrug sources of the free nucleosides and their 5'-monophosphates. Evidently, the phosphonates and phosphonothionates are not similarly cleaved, nor are they phosphorylated to form antivirally active or cytotoxic products. The importance of intracellular formation of these products in the activation of 12-17 is less clear. Potential prodrugs 4-17 are all stable in aqueous solution for hours with the exception of 14. Conjugates 4-17 showed no activity against a series of DNA and RNA viruses.
|
Concentration required to protect 50% of HIV-2 infected MT-4 cells against viral cytopathicity.
|
Human immunodeficiency virus 2
|
690.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential prodrug derivatives of 2',3'-didehydro-2',3'-dideoxynucleosides. Preparations and antiviral activities.
Year : 1992
Volume : 35
Issue : 15
First Page : 2728
Last Page : 2735
Authors : Mullah KB, Rao TS, Balzarini J, De Clercq E, Bentrude WG.
Abstract : The preparations and antiviral activities of a series (4-17) of potential prodrug forms of the antivirals 2',3'-didehydro-2',3'-dideoxyadenosine (D4A) and 2',3'-didehydro-2',3'-dideoxycytosine (D4C) are reported. The 5'-phenyl- and 5'-methylphosphonates (4, 6, 8, and 10) and their phosphonothionate congeners (5, 7, 9, and 11), with the exception of 10, were inactive in vitro against HIV-1 and HIV-2. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. This strongly suggests that the diesters are hydrolyzed to the nucleosides D4A and D4C and/or their 5'-monophosphates. The facile hydrolysis of 12 and 13 to these products was demonstrated in a medium containing 10% fetal calf serum. The molecules can serve as ready prodrug sources of the free nucleosides and their 5'-monophosphates. Evidently, the phosphonates and phosphonothionates are not similarly cleaved, nor are they phosphorylated to form antivirally active or cytotoxic products. The importance of intracellular formation of these products in the activation of 12-17 is less clear. Potential prodrugs 4-17 are all stable in aqueous solution for hours with the exception of 14. Conjugates 4-17 showed no activity against a series of DNA and RNA viruses.
|
Effective concentration that increases formazan production in infected MT-2 cells
|
Homo sapiens
|
0.29
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides.
Year : 1990
Volume : 33
Issue : 1
First Page : 17
Last Page : 21
Authors : Vince R, Hua M.
Abstract : (+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.
|
Compound was tested for its inhibitory activity against HIV replication in MT-2 cells.
|
Homo sapiens
|
0.44
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV activity of 4'-thio-2',3'-dideoxynucleosides.
Year : 1992
Volume : 35
Issue : 3
First Page : 533
Last Page : 538
Authors : Secrist JA, Riggs RM, Tiwari KN, Montgomery JA.
Abstract : A series of 2',3'-dideoxy-4'-thionucleoside analogues of purines and pyrimidines, including 4'-thioddI (17), 4'-thioddC (27), and 4'-thioAZT (34), were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). A stereospecific synthesis of the 2,3-dideoxy-4-thioribofuranosyl carbohydrate precursor 11 starting with L-glutamic acid is described. 2',3'-Dideoxy-4'-thiocytidine (27) displayed significant, but modest activity in vitro against human immunodeficiency virus.
|
Inhibitory concentration that reduces formazan production in infected MT-2 cells.
|
Homo sapiens
|
44.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides.
Year : 1990
Volume : 33
Issue : 1
First Page : 17
Last Page : 21
Authors : Vince R, Hua M.
Abstract : (+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.
|
Effective concentration for 50% protection of HIV-induced cytopathogenicity in MT-4 cells on the MTT assay
|
None
|
88.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140.
Year : 2001
Volume : 11
Issue : 14
First Page : 1897
Last Page : 1902
Authors : Tamamura H, Omagari A, Hiramatsu K, Gotoh K, Kanamoto T, Xu Y, Kodama E, Matsuoka M, Hattori T, Yamamoto N, Nakashima H, Otaka A, Fujii N.
Abstract : We previously reported a truncated polyphemusin peptide analogue, T140, which efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. We have found that T140 is not stable in feline serum due to the cleavage of the C-terminal Arg,(14) indispensable for anti-HIV activity. On the other hand, a C-terminally amidated analogue of T140, TZ14004, has been found to be completely stable in incubation in the serum for 2 days. The C-terminal amide is thought to be needed for stability in serum. However, TZ14004 does not have fairly strong anti-HIV activity, but has relatively strong cytotoxicity, probably due to an increase by +1 charge from total +7 charges of T140. In our previous study, the number of total +6 charges seemed to be a suitable balance between activity and cytotoxicity. In this study, we have conducted a double-L-citrulline (Cit)-scanning study on TZ14004 based on the C-terminally amidated form in due consideration of the total net charges in the whole molecule to find novel effective CXCR4 inhibitors, TN14003 ([Cit(6)]-T140 with the C-terminal amide) and TC14012 ([Cit(6), D-Cit(8)]-T140 with the C-terminal amide), which possess high selectivity indexes (SIs) and complete stability in feline serum.
|
AntiHIV-1 activity measured in MT-4 cells at 5 to 6 different concentrations, using the P24 antigen enzyme-linked immunosorbent assay (ELISA).
|
Homo sapiens
|
236.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC).
Year : 1990
Volume : 33
Issue : 8
First Page : 2145
Last Page : 2150
Authors : Watanabe KA, Harada K, Zeidler J, Matulic-Adamic J, Takahashi K, Ren WY, Cheng LC, Fox JJ, Chou TC, Zhu QY.
Abstract : 1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.
|
AntiHIV-1 activity measured in MT-4 cells at 5 to 6 different concentrations, using the reverse transcriptase (RT) assay
|
Homo sapiens
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC).
Year : 1990
Volume : 33
Issue : 8
First Page : 2145
Last Page : 2150
Authors : Watanabe KA, Harada K, Zeidler J, Matulic-Adamic J, Takahashi K, Ren WY, Cheng LC, Fox JJ, Chou TC, Zhu QY.
Abstract : 1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.
|
Anti-HIV activity against HIV-I A17 strain in MT2 cell line
|
Homo sapiens
|
331.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers.
Year : 1996
Volume : 39
Issue : 6
First Page : 1303
Last Page : 1313
Authors : Flavin MT, Rizzo JD, Khilevich A, Kucherenko A, Sheinkman AK, Vilaychack V, Lin L, Chen W, Greenwood EM, Pengsuparp T, Pezzuto JM, Hughes SH, Flavin TM, Cibulski M, Boulanger WA, Shone RL, Xu ZQ.
Abstract : The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
|
Anti-HIV activity against HIV-I G910-6 strain in MT2 cell line
|
Homo sapiens
|
994.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers.
Year : 1996
Volume : 39
Issue : 6
First Page : 1303
Last Page : 1313
Authors : Flavin MT, Rizzo JD, Khilevich A, Kucherenko A, Sheinkman AK, Vilaychack V, Lin L, Chen W, Greenwood EM, Pengsuparp T, Pezzuto JM, Hughes SH, Flavin TM, Cibulski M, Boulanger WA, Shone RL, Xu ZQ.
Abstract : The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
|
Anti-HIV activity against HIV-I IIIB strain in MT2 cell line
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers.
Year : 1996
Volume : 39
Issue : 6
First Page : 1303
Last Page : 1313
Authors : Flavin MT, Rizzo JD, Khilevich A, Kucherenko A, Sheinkman AK, Vilaychack V, Lin L, Chen W, Greenwood EM, Pengsuparp T, Pezzuto JM, Hughes SH, Flavin TM, Cibulski M, Boulanger WA, Shone RL, Xu ZQ.
Abstract : The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
|
Concentration required to achieve 50% protection of MT-4 cells against cytopathic effect of HIV-1
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine.
Year : 1989
Volume : 32
Issue : 12
First Page : 2507
Last Page : 2509
Authors : Miyasaka T, Tanaka H, Baba M, Hayakawa H, Walker RT, Balzarini J, De Clercq E.
|
Effective conc. required to achieve 50% inhibition of HIV-1 IIIB multiplication in PBM (peripheral blood mononuclear) cells
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase.
Year : 2000
Volume : 43
Issue : 10
First Page : 1927
Last Page : 1939
Authors : Pontikis R, Dollé V, Guillaumel J, Dechaux E, Note R, Nguyen CH, Legraverend M, Bisagni E, Aubertin AM, Grierson DS, Monneret C.
Abstract : To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. In marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC(50) = 0.45 microM) against HIV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was observed for these bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respective sites. Interestingly, however, the results indicate that the AZT-HEPT conjugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the former compounds interact preferentially with the hydrophobic pocket in RT, whereas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.
|
Effective conc. required to achieve 50% inhibition of HIV-2 D194 multiplication in PBM (peripheral blood mononuclear) cells
|
Homo sapiens
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase.
Year : 2000
Volume : 43
Issue : 10
First Page : 1927
Last Page : 1939
Authors : Pontikis R, Dollé V, Guillaumel J, Dechaux E, Note R, Nguyen CH, Legraverend M, Bisagni E, Aubertin AM, Grierson DS, Monneret C.
Abstract : To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. In marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC(50) = 0.45 microM) against HIV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was observed for these bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respective sites. Interestingly, however, the results indicate that the AZT-HEPT conjugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the former compounds interact preferentially with the hydrophobic pocket in RT, whereas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.
|
Inhibition of Tomioka strain of herpes simplex virus( Tomioka strain of HSV-1) by quantitative CPE reduction assay in vero cells
|
Human herpesvirus 1
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiviral activity of novel acyclic nucleosides: discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses.
Year : 1998
Volume : 41
Issue : 8
First Page : 1284
Last Page : 1298
Authors : Sekiyama T, Hatsuya S, Tanaka Y, Uchiyama M, Ono N, Iwayama S, Oikawa M, Suzuki K, Okunishi M, Tsuji T.
Abstract : A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated for their antiherpetic activity. Among those, 9-[[cis-1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a) exhibited strong antiherpetic activity (IC50 of 0.020 microg/mL against HSV-1 Tomioka vs 0.81 microg/mL for acyclovir). Enantiomer 3a was also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity in this series of compounds is discussed.
|
Inhibitory constant against HIV-1 reverse transcriptase
|
Human immunodeficiency virus 1
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2',3'-dideoxynucleoside 5'-alpha-P-borano-beta,gamma-(difluoromethylene)triphosphates and their inhibition of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 7
First Page : 2695
Last Page : 2700
Authors : Boyle NA, Rajwanshi VK, Prhavc M, Wang G, Fagan P, Chen F, Ewing GJ, Brooks JL, Hurd T, Leeds JM, Bruice TW, Cook PD.
Abstract : The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.
|
Effective concentration to inhibit 50% of human immunodeficiency virus replication in a cell culture model
|
None
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiviral activity of helioxanthin analogues.
Year : 2005
Volume : 48
Issue : 2
First Page : 534
Last Page : 546
Authors : Yeo H, Li Y, Fu L, Zhu JL, Gullen EA, Dutschman GE, Lee Y, Chung R, Huang ES, Austin DJ, Cheng YC.
Abstract : A series of natural product analogues based on helioxanthin (2), with particular attention to modification of the lactone ring and methylenedioxy group, were synthesized and evaluated for their antiviral activities. Among them, lactam derivative 18 and helioxanthin cyclic hydrazide 28 exhibited significant in vitro antiviral activity against hepatitis B virus (EC(50) = 0.08 and 0.03 microM, respectively). Compound 18 showed the most potent antiviral activity against hepatitis C virus (55% inhibition at 1.0 microM). Compound 12, an acid-hydrolyzed product of helioxanthin cyclic imide derivative 9, was found to exhibit broad-spectrum antiviral activity against hepatitis B virus (EC(50) = 0.8 microM), herpes simplex virus type 1 (EC(50) = 0.15 microM) and type 2 (EC(50) < 0.1 microM), Epstein-Barr virus (EC(50) = 9.0 microM), and cytomegalovirus (EC(50) = 0.45 microM). Helioxanthin lactam derivative 18 also showed marked inhibition of herpes simplex virus type 1 (EC(50) = 0.29 microM) and type 2 (EC(50) = 0.16 microM). The cyclic hydrazide derivative of helioxanthin 28 and its brominated product 42 exhibited moderately potent activities against human immunodeficiency virus (EC(50) = 2.7 and 2.5 microM, respectively). Collectively, these molecules represent a novel set of antiviral compounds with unique structural features.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Ra at 100 uM by microplate alamar blue assay
|
Mycobacterium tuberculosis
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides.
Year : 2007
Volume : 50
Issue : 19
First Page : 4766
Last Page : 4774
Authors : Rai D, Johar M, Srivastav NC, Manning T, Agrawal B, Kunimoto DY, Kumar R.
Abstract : The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro-2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3'-Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5-tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3'-dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3'-dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio-2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d-glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d-glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively.
|
Antimycobacterial activity against Mycobacterium bovis BCG at 100 uM by microplate alamar blue assay
|
Mycobacterium bovis BCG
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides.
Year : 2007
Volume : 50
Issue : 19
First Page : 4766
Last Page : 4774
Authors : Rai D, Johar M, Srivastav NC, Manning T, Agrawal B, Kunimoto DY, Kumar R.
Abstract : The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro-2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3'-Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5-tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3'-dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3'-dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio-2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d-glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d-glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively.
|
Antimycobacterial activity against Mycobacterium avium ATCC 25291 at 100 uM by microplate alamar blue assay
|
Mycobacterium avium
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides.
Year : 2007
Volume : 50
Issue : 19
First Page : 4766
Last Page : 4774
Authors : Rai D, Johar M, Srivastav NC, Manning T, Agrawal B, Kunimoto DY, Kumar R.
Abstract : The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro-2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3'-Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5-tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3'-dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3'-dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio-2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d-glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d-glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.1
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : New saponins from the starfish Certonardoa semiregularis.
Year : 2002
Volume : 65
Issue : 11
First Page : 1649
Last Page : 1656
Authors : Wang W, Li F, Alam N, Liu Y, Hong J, Lee CK, Im KS, Jung JH.
Abstract : Ten new saponins designated as certonardosides A-J (1-5, 7-11) and the known halityloside D (6) were isolated from the brine shrimp active fraction of the MeOH extract of the starfish Certonardoa semiregularis. The structures were determined on the basis of spectral analysis and chemical manipulation. The compounds were evaluated for antiviral activity against HIV, HSV, CoxB, EMCV, and VSV and displayed insignificant activity within the range of noncytotoxic concentrations.
|
Antiviral activity against HIV2 ROD infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 2
|
0.1
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : New saponins from the starfish Certonardoa semiregularis.
Year : 2002
Volume : 65
Issue : 11
First Page : 1649
Last Page : 1656
Authors : Wang W, Li F, Alam N, Liu Y, Hong J, Lee CK, Im KS, Jung JH.
Abstract : Ten new saponins designated as certonardosides A-J (1-5, 7-11) and the known halityloside D (6) were isolated from the brine shrimp active fraction of the MeOH extract of the starfish Certonardoa semiregularis. The structures were determined on the basis of spectral analysis and chemical manipulation. The compounds were evaluated for antiviral activity against HIV, HSV, CoxB, EMCV, and VSV and displayed insignificant activity within the range of noncytotoxic concentrations.
|
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
|
1.0
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
|
1.0
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 infected in human MT2 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
130.0
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 HIV1 infected in human PBMC assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
200.0
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.
|
Mitochondrial toxicity in human HepG2 cells assessed as percent inhibition of mitochondrial DNA at 10 uM after 14 days by real-time PCR
|
Homo sapiens
|
99.88
%
|
|
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.
|
Mitochondrial toxicity in human HepG2 cells assessed as percent inhibition of beta-actin DNA at 10 uM after 14 days by real-time PCR
|
Homo sapiens
|
61.39
%
|
|
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 HIV1 3B infected in human MT4 cells coinjected with HTLV1 assessed as reduction in virus induced cytopathicity measured 5 days post infection by MTT assay
|
Human immunodeficiency virus 1
|
0.043
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation.
Year : 2011
Volume : 19
Issue : 13
First Page : 3945
Last Page : 3955
Authors : Park AY, Kim WH, Kang JA, Lee HJ, Lee CK, Moon HR.
Abstract : Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti-AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.
|
Antiviral activity against HIV2 ROD infected in human MT4 cells assessed as reduction in virus induced cytopathicity measured 5 days post infection by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
0.04
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation.
Year : 2011
Volume : 19
Issue : 13
First Page : 3945
Last Page : 3955
Authors : Park AY, Kim WH, Kang JA, Lee HJ, Lee CK, Moon HR.
Abstract : Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti-AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.
|
Antiviral activity against HIV-1 3B infected in human MT4 cells assessed as inhibition of virus-induced syncytium formation after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
750.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Arylazolylthioacetanilide. Part 8: Design, synthesis and biological evaluation of novel 2-(2-(2,4-dichlorophenyl)-2H-1,2,4-triazol-3-ylthio)-N-arylacetamides as potent HIV-1 inhibitors.
Year : 2011
Volume : 46
Issue : 10
First Page : 5039
Last Page : 5045
Authors : Zhan P, Chen X, Li X, Li D, Tian Y, Chen W, Pannecouque C, De Clercq E, Liu X.
Abstract : The development of novel HIV-1 NNRTIs offers the possibility of generating novel structures with increased potency. Based on the bioisosteric principle, a novel series of 2-(2-(2,4-dichlorophenyl)-2H-1,2,4-triazol-3-ylthio)-N-arylacetamide derivatives were designed, synthesized using a simple and efficient synthetic route, structurally confirmed by spectral analysis, evaluated for their anti-HIV activity in MT-4 cells and their inhibitory effect on HIV-1 RT. The results showed that some of the new compounds displayed low micromolar potency for inhibiting HIV-1 replication and promising activities against several selected resistant strains that confer resistance to current NNRTIs. However, all newly synthesized derivatives were not active against HIV-2 replication.
|
Antiviral activity against HIV-2 ROD infected in human MT4 cells assessed as inhibition of virus-induced syncytium formation after 5 days by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
880.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Arylazolylthioacetanilide. Part 8: Design, synthesis and biological evaluation of novel 2-(2-(2,4-dichlorophenyl)-2H-1,2,4-triazol-3-ylthio)-N-arylacetamides as potent HIV-1 inhibitors.
Year : 2011
Volume : 46
Issue : 10
First Page : 5039
Last Page : 5045
Authors : Zhan P, Chen X, Li X, Li D, Tian Y, Chen W, Pannecouque C, De Clercq E, Liu X.
Abstract : The development of novel HIV-1 NNRTIs offers the possibility of generating novel structures with increased potency. Based on the bioisosteric principle, a novel series of 2-(2-(2,4-dichlorophenyl)-2H-1,2,4-triazol-3-ylthio)-N-arylacetamide derivatives were designed, synthesized using a simple and efficient synthetic route, structurally confirmed by spectral analysis, evaluated for their anti-HIV activity in MT-4 cells and their inhibitory effect on HIV-1 RT. The results showed that some of the new compounds displayed low micromolar potency for inhibiting HIV-1 replication and promising activities against several selected resistant strains that confer resistance to current NNRTIs. However, all newly synthesized derivatives were not active against HIV-2 replication.
|
Antiviral activity against HIV2 ROD infected in MT4 cells assessed as inhibition of virus-induced cytopathogenicity by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
0.19
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis of novel biologically active methylene derivatives of sydnones
Year : 2013
Volume : 22
Issue : 12
First Page : 5752
Last Page : 5763
Authors : Asundaria ST, Pannecouque C, De Clercq E, Supuran CT, Patel KC
|
Antiviral activity against HIV1 3B infected in MT4 cells assessed as inhibition of virus-induced cytopathogenicity by MTT assay
|
Human immunodeficiency virus 1
|
0.16
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis of novel biologically active methylene derivatives of sydnones
Year : 2013
Volume : 22
Issue : 12
First Page : 5752
Last Page : 5763
Authors : Asundaria ST, Pannecouque C, De Clercq E, Supuran CT, Patel KC
|
Antiviral activity against Human immunodeficiency virus 2 ROD infected in MT4 cells assessed as inhibition of virus-induced cytopathogenicity by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
400.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Efficient synthesis of 3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3,3'-dione as novel skeletons specifically for influenza virus type B inhibition.
Year : 2013
Volume : 62
First Page : 534
Last Page : 544
Authors : Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.
Abstract : An efficient and novel two step synthetic procedure to prepare various substituted 3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3,3'-diones A, was established from very simple and easily available starting materials. The developed method is a robust and general approach for the synthesis of these structures. The prepared compounds were tested against influenza virus type A viz., A/Taiwan/1/86 (H1N1), A/Hong Kong/8/68 (H3N2) and type B viz., B/Panama/45/90, B/Taiwan/2/62, B/Lee/40, B/Brisbane/60/2008. Among 31 compounds tested, some of them showed good activity (selective index values >10) against these influenza viruses preferentially for type B. The most active compound 3b showed activity in 3.0-16.1 μM range with a selectivity index value between 30 and 166 against these type B viruses, in which it was comparable to the antiviral agent favipiravir. Also, 3b is found to be inactive against other enveloped viruses (viz., HIV and HSV) showing its specificity for influenza viruses.
|
Antiviral activity against Human immunodeficiency virus 1 3B infected in MT4 cells assessed as inhibition of virus-induced cytopathogenicity by MTT assay
|
Human immunodeficiency virus 1
|
400.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Efficient synthesis of 3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3,3'-dione as novel skeletons specifically for influenza virus type B inhibition.
Year : 2013
Volume : 62
First Page : 534
Last Page : 544
Authors : Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.
Abstract : An efficient and novel two step synthetic procedure to prepare various substituted 3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3,3'-diones A, was established from very simple and easily available starting materials. The developed method is a robust and general approach for the synthesis of these structures. The prepared compounds were tested against influenza virus type A viz., A/Taiwan/1/86 (H1N1), A/Hong Kong/8/68 (H3N2) and type B viz., B/Panama/45/90, B/Taiwan/2/62, B/Lee/40, B/Brisbane/60/2008. Among 31 compounds tested, some of them showed good activity (selective index values >10) against these influenza viruses preferentially for type B. The most active compound 3b showed activity in 3.0-16.1 μM range with a selectivity index value between 30 and 166 against these type B viruses, in which it was comparable to the antiviral agent favipiravir. Also, 3b is found to be inactive against other enveloped viruses (viz., HIV and HSV) showing its specificity for influenza viruses.
|
Antiviral activity against wild type HIV-1 3B infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
460.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Towards new C6-rigid S-DABO HIV-1 reverse transcriptase inhibitors: synthesis, biological investigation and molecular modeling studies.
Year : 2013
Volume : 21
Issue : 21
First Page : 6477
Last Page : 6483
Authors : Wu HQ, Yan ZH, Chen WX, He QQ, Chen FE, De Clercq E, Balzarini J, Daelemans D, Pannecouque C.
Abstract : A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC50 value of 0.26μM and a selectivity index (SI) of 541. The preliminary structure-activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed.
|
Antiviral activity against HIV-2 ROD infected in human CEM/0 cells
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
500.0
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 wild-type HIV-1 3B infected in human MT4 cells assessed as protection against virus-induced cytopathic effect measured 5 days post-infection by MTT assay
|
Human immunodeficiency virus 1
|
570.0
nM
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of new conformationally restricted S-DABO hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase
Year : 2014
Volume : 5
Issue : 4
First Page : 468
Last Page : 473
Authors : Wu H, Pannecouque C, Yan Z, Chen W, He Q, Chen F, Balzarini J, Daelemans D, De Clercq E
|
Antiviral activity against HIV1 infected in human H9 cells assessed as protection against virus-induced cytopathic effect by tetrazolium reduction based colorimetric technique
|
Human immunodeficiency virus 1
|
79.0
nM
|
|
Journal : J. Nat. Prod.
Title : Sesquiterpenoid tropolone glycosides from Liriosma ovata.
Year : 2015
Volume : 78
Issue : 2
First Page : 315
Last Page : 319
Authors : Ma J, Pawar RS, Grundel E, Mazzola EP, Ridge CD, Masaoka T, Le Grice SF, Wilson J, Beutler JA, Krynitsky AJ.
Abstract : Two new sesquiterpenoid tropolone glycosides, liriosmasides A (1) and B (2), along with two known compounds, secoxyloganin and oplopanpheside C, were isolated from a methanol extract of the roots of Liriosma ovata. The structures of 1 and 2 were elucidated by spectroscopic methods including 1D and 2D NMR and by high-resolution mass spectrometry involving an ultra-high-performance liquid chromatography-quadrupole-orbital ion trap mass spectrometric (UHPLC-Q-Orbitrap MS) method. Compound 1 showed weak inhibitory activity against HIV RNase H.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as protection against virus-induced cytopathic effect after 5 days MTT assay
|
Human immunodeficiency virus 1
|
0.16
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells.
Year : 2016
Volume : 121
First Page : 58
Last Page : 70
Authors : Kulabaş N, Tatar E, Bingöl Özakpınar Ö, Özsavcı D, Pannecouque C, De Clercq E, Küçükgüzel İ.
Abstract : In this study, a series of thiosemicarbazide derivatives 12-14, 1,2,4-triazol-3-thione derivatives 15-17 and compounds bearing 2-(4H-1,2,4-triazole-3-ylthio)acetamide structure 18-32 have been synthesized starting from phenolic compounds such as 2-naphthol, paracetamol and thymol. Structures and purity of the target compounds were confirmed by the use of their chromatographic and spectral data besides microanalysis. All of the synthesized new compounds 12-32 were evaluated for their anti-HIV activity. Among these compounds, three representatives 18, 19 and 25 were selected and evaluated by the National Cancer Institute (NCI) against the full panel of 60 human cancer cell lines derived from nine different cancer types. Antiproliferative effects of the selected compounds were demonstrated in human tumor cell lines K-562, A549 and PC-3. These compounds inhibited cell growth assessed by MTT assay. Compound 18, 19 and 25 exhibited anti-cancer activity with IC50 values of 5.96 μM (PC-3 cells), 7.90 μM (A549/ATCC cells) and 7.71 μM (K-562 cells), respectively. After the cell viability assay, caspase activation and Bcl-2 activity of the selected compounds were measured and the loss of mitochondrial membrane potential (MMP) was detected. Compounds 18, 19 and 25 showed a significant increase in caspase-3 activity in a dose-dependent manner. This was not observed for caspase-8 activity with compound 18 and 25, while compound 19 was significantly elevated only at the dose of 50 μM. In addition, all three compounds significantly decreased the mitochondrial membrane potential and expression of Bcl-2.
|
Antiviral activity against HIV2 ROD infected in human MT4 cells assessed as protection against virus-induced cytopathic effect after 5 days MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
0.19
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells.
Year : 2016
Volume : 121
First Page : 58
Last Page : 70
Authors : Kulabaş N, Tatar E, Bingöl Özakpınar Ö, Özsavcı D, Pannecouque C, De Clercq E, Küçükgüzel İ.
Abstract : In this study, a series of thiosemicarbazide derivatives 12-14, 1,2,4-triazol-3-thione derivatives 15-17 and compounds bearing 2-(4H-1,2,4-triazole-3-ylthio)acetamide structure 18-32 have been synthesized starting from phenolic compounds such as 2-naphthol, paracetamol and thymol. Structures and purity of the target compounds were confirmed by the use of their chromatographic and spectral data besides microanalysis. All of the synthesized new compounds 12-32 were evaluated for their anti-HIV activity. Among these compounds, three representatives 18, 19 and 25 were selected and evaluated by the National Cancer Institute (NCI) against the full panel of 60 human cancer cell lines derived from nine different cancer types. Antiproliferative effects of the selected compounds were demonstrated in human tumor cell lines K-562, A549 and PC-3. These compounds inhibited cell growth assessed by MTT assay. Compound 18, 19 and 25 exhibited anti-cancer activity with IC50 values of 5.96 μM (PC-3 cells), 7.90 μM (A549/ATCC cells) and 7.71 μM (K-562 cells), respectively. After the cell viability assay, caspase activation and Bcl-2 activity of the selected compounds were measured and the loss of mitochondrial membrane potential (MMP) was detected. Compounds 18, 19 and 25 showed a significant increase in caspase-3 activity in a dose-dependent manner. This was not observed for caspase-8 activity with compound 18 and 25, while compound 19 was significantly elevated only at the dose of 50 μM. In addition, all three compounds significantly decreased the mitochondrial membrane potential and expression of Bcl-2.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA levels at 10 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
96.0
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Cytotoxicity against human HepG2 cells assessed as inhibition of nuclear DNA levels at 10 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
53.0
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
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
|
4.24
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-9.44
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
8.0
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
1.57
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
3.66
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
0.46
%
|
|
|
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
|
-0.26
%
|
|
|
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
|
0.17
%
|
|
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.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA level at 10 uM followed by medium plus drugs replenishment every 3 to 4 days for 14 days relative to control
|
Homo sapiens
|
84.0
%
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of nuclear ribosomal-DNA level at 10 uM followed by medium plus drugs replenishment every 3 to 4 days for 14 days relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.63
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.14
%
|
|
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
|
0.0
%
|
|
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
|
-0.04
%
|
|
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
|
-0.04
%
|
|
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
|
0.0
%
|
|
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 HIV-1 infected in human CEM-SS cells assessed as reduction in viral multiplication by measuring decrease in reverse transcriptase activity incubated for 5 days
|
Human immunodeficiency virus 1
|
67.0
nM
|
|
|
Antiviral activity against HIV-1 infected in human CEM-SS cells assessed as reduction in viral multiplication by measuring decrease in reverse transcriptase activity incubated for 5 days in presence of AZT
|
Human immunodeficiency virus 1
|
16.0
nM
|
|
|
Antiviral activity against HIV-1 infected in human CEM-SS cells assessed as reduction in viral multiplication by measuring decrease in reverse transcriptase activity incubated for 5 days in presence of ddA
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
|
Antiviral activity against HIV-1 infected in human MT4 cells assessed as reduction in virus-indued cytopathogenicity incubated for 5 days in presence of AZT by MTT assay
|
Human immunodeficiency virus 1
|
83.0
nM
|
|
|
Antiviral activity against HIV-1 infected in human CEM-TK(-) cells assessed as reduction in viral multiplication by measuring decrease in reverse transcriptase activity incubated for 6 days
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
|
Antiviral activity against HIV-1 infected in human CEM-TK(-) cells assessed as reduction in viral multiplication by measuring decrease in reverse transcriptase activity incubated for 6 days in presence of AZT
|
Human immunodeficiency virus 1
|
9.0
nM
|
|
