|
In vitro antitumor activity against A549 human NSCLC lung carcinoma cells
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of heterocyclic analogues of mycophenolic acid as potential chemotherapeutic agents
Year : 1995
Volume : 5
Issue : 8
First Page : 861
Last Page : 866
Authors : Lee J, Anderson WK
|
In vitro secondary T-cell (CEM) proliferation assay
|
Homo sapiens
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4- morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity.
Year : 2002
Volume : 45
Issue : 11
First Page : 2127
Last Page : 2130
Authors : Dhar TG, Shen Z, Guo J, Liu C, Watterson SH, Gu HH, Pitts WJ, Fleener CA, Rouleau KA, Sherbina NZ, McIntyre KW, Shuster DJ, Witmer MR, Tredup JA, Chen BC, Zhao R, Bednarz MS, Cheney DL, MacMaster JF, Miller LM, Berry KK, Harper TW, Barrish JC, Hollenbaugh DL, Iwanowicz EJ.
Abstract : Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.
|
Inhibition of CEM (human leukemia) cell proliferation.
|
Homo sapiens
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.
Year : 2003
Volume : 13
Issue : 20
First Page : 3557
Last Page : 3560
Authors : Dhar TG, Shen Z, Gu HH, Chen P, Norris D, Watterson SH, Ballentine SK, Fleener CA, Rouleau KA, Barrish JC, Townsend R, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.
|
Cytotoxic activity against HIV uninfected T4 lymphocytes (CEM cell line)
|
Homo sapiens
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of heterocyclic analogues of mycophenolic acid as potential chemotherapeutic agents
Year : 1995
Volume : 5
Issue : 8
First Page : 861
Last Page : 866
Authors : Lee J, Anderson WK
|
Inhibitory activity against CEM cell proliferation
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel inhibitors of IMPDH: a highly potent and selective quinolone-based series.
Year : 2003
Volume : 13
Issue : 3
First Page : 543
Last Page : 546
Authors : Watterson SH, Carlsen M, Dhar TG, Shen Z, Pitts WJ, Guo J, Gu HH, Norris D, Chorba J, Chen P, Cheney D, Witmer M, Fleener CA, Rouleau K, Townsend R, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
|
Inhibitory activity against proliferation of CEM cell line
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolone-based IMPDH inhibitors: introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues.
Year : 2003
Volume : 13
Issue : 3
First Page : 547
Last Page : 551
Authors : Dhar TG, Watterson SH, Chen P, Shen Z, Gu HH, Norris D, Carlsen M, Haslow KD, Pitts WJ, Guo J, Chorba J, Fleener CA, Rouleau KA, Townsend R, Hollenbaugh D, Iwanowicz EJ.
Abstract : The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.
|
Inhibitory activity of compound against HT-29 human colon adenocarcinoma cell line
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and modeling studies with monocyclic analogues of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 1
First Page : 46
Last Page : 55
Authors : Anderson WK, Boehm TL, Makara GM, Swann RT.
Abstract : Two stepwise procedures, developed for the introduction of the (E)-4-methyl-4-hexenoic acid side chain of mycophenolic acid, were used in the synthesis of monocyclic mycophenolic acid analogues 2a-i. The derivatives with a methyl group or hydrogen at C-4 and lacking the lactone moiety were much less cytotoxic than mycophenolic acid. The monocyclic analogues with a C-4 chloro group did show some activity, albeit much less than mycophenolic acid. The observed differences in potency are rationalized by semiempirical calculations of intramolecular H-bonds.
|
In vitro antitumor activity against HT-29 human colon adenocarcinoma cells
|
Homo sapiens
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of heterocyclic analogues of mycophenolic acid as potential chemotherapeutic agents
Year : 1995
Volume : 5
Issue : 8
First Page : 861
Last Page : 866
Authors : Lee J, Anderson WK
|
Inhibition of human Lymphocyte proliferation. The IC50 values were determined by interpolation using cubic spline determination.
|
Homo sapiens
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
In vitro inhibition of human lymphocyte proliferation in response to phytohemagglutininin (PHA) was determined
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.
Year : 1990
Volume : 33
Issue : 2
First Page : 833
Last Page : 838
Authors : Nelson PH, Eugui E, Wang CC, Allison AC.
Abstract : The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.
|
In vitro inhibition of human lymphocyte proliferation in response to pokeweed mitogen(PWM) was determined
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.
Year : 1990
Volume : 33
Issue : 2
First Page : 833
Last Page : 838
Authors : Nelson PH, Eugui E, Wang CC, Allison AC.
Abstract : The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.
|
In vitro inhibition of human lymphocyte proliferation in response to staphylococcus protein A(SPA) was determined
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.
Year : 1990
Volume : 33
Issue : 2
First Page : 833
Last Page : 838
Authors : Nelson PH, Eugui E, Wang CC, Allison AC.
Abstract : The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.
|
Inhibition of Inosine Monophosphate Dehydrogenase II (IMPDH II)
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A survey of cyclic replacements for the central diamide moiety of inhibitors of inosine monophosphate dehydrogenase.
Year : 2002
Volume : 12
Issue : 21
First Page : 3125
Last Page : 3128
Authors : Dhar TG, Liu C, Pitts WJ, Guo J, Watterson SH, Gu H, Fleener CA, Rouleau K, Sherbina NZ, Barrish JC, Hollenbaugh D, Iwanowicz EJ.
Abstract : A series of heterocyclic replacements for the central diamide moiety of 1, a potent small molecule inhibitor of inosine monophosphate dehydrogenase (IMPDH) were explored The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for these new series of inhibitors is given.
|
In vitro inhibition of inosine Inosine-5'-monophosphate dehydrogenase
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.
Year : 1990
Volume : 33
Issue : 2
First Page : 833
Last Page : 838
Authors : Nelson PH, Eugui E, Wang CC, Allison AC.
Abstract : The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.
|
Inhibitory activity against inosine monophosphate dehydrogenase IMPDH type I
|
None
|
55.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel inhibitors of IMPDH: a highly potent and selective quinolone-based series.
Year : 2003
Volume : 13
Issue : 3
First Page : 543
Last Page : 546
Authors : Watterson SH, Carlsen M, Dhar TG, Shen Z, Pitts WJ, Guo J, Gu HH, Norris D, Chorba J, Chen P, Cheney D, Witmer M, Fleener CA, Rouleau K, Townsend R, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
|
Inhibitory activity against human Inosine-5'-monophosphate dehydrogenase 1 (IMPDH type I isoform); Range is 33-37 nM
|
None
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.
Year : 1998
Volume : 41
Issue : 4
First Page : 618
Last Page : 622
Authors : Lesiak K, Watanabe KA, Majumdar A, Powell J, Seidman M, Vanderveen K, Goldstein BM, Pankiewicz KW.
Abstract : Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropy-lidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (Ki = 0.3 microM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 microM). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.
|
Inhibitory activity against human Inosine-5'-monophosphate dehydrogenase 1 (IMPDH type I)
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia.
Year : 2002
Volume : 45
Issue : 3
First Page : 703
Last Page : 712
Authors : Pankiewicz KW, Lesiak-Watanabe KB, Watanabe KA, Patterson SE, Jayaram HN, Yalowitz JA, Miller MD, Seidman M, Majumdar A, Prehna G, Goldstein BM.
Abstract : Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.
|
Compound was tested for inhibition of human recombinant type II Inosine Monophosphate Dehydrogenase at pH 7.4
|
None
|
25.1
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
Compound was tested for inhibition of human recombinant type II Inosine Monophosphate Dehydrogenase at pH 8.0
|
None
|
24.8
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
Inhibition of human inosine-5'-monophosphate dehydrogenase 2
|
None
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4- morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity.
Year : 2002
Volume : 45
Issue : 11
First Page : 2127
Last Page : 2130
Authors : Dhar TG, Shen Z, Guo J, Liu C, Watterson SH, Gu HH, Pitts WJ, Fleener CA, Rouleau KA, Sherbina NZ, McIntyre KW, Shuster DJ, Witmer MR, Tredup JA, Chen BC, Zhao R, Bednarz MS, Cheney DL, MacMaster JF, Miller LM, Berry KK, Harper TW, Barrish JC, Hollenbaugh DL, Iwanowicz EJ.
Abstract : Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.
|
Inhibition of human inosine monophosphate dehydrogenase IMPDH II
|
None
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel inhibitors of IMPDH: a highly potent and selective quinolone-based series.
Year : 2003
Volume : 13
Issue : 3
First Page : 543
Last Page : 546
Authors : Watterson SH, Carlsen M, Dhar TG, Shen Z, Pitts WJ, Guo J, Gu HH, Norris D, Chorba J, Chen P, Cheney D, Witmer M, Fleener CA, Rouleau K, Townsend R, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
|
Inhibitory activity against inosine monophosphate dehydrogenase IMPDH II
|
None
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolone-based IMPDH inhibitors: introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues.
Year : 2003
Volume : 13
Issue : 3
First Page : 547
Last Page : 551
Authors : Dhar TG, Watterson SH, Chen P, Shen Z, Gu HH, Norris D, Carlsen M, Haslow KD, Pitts WJ, Guo J, Chorba J, Fleener CA, Rouleau KA, Townsend R, Hollenbaugh D, Iwanowicz EJ.
Abstract : The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.
|
Inhibition of human Inosine-5'-monophosphate dehydrogenase 2
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase.
Year : 2002
Volume : 12
Issue : 16
First Page : 2137
Last Page : 2140
Authors : Pitts WJ, Guo J, Dhar TG, Shen Z, Gu HH, Watterson SH, Bednarz MS, Chen BC, Barrish JC, Bassolino D, Cheney D, Fleener CA, Rouleau KA, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.
|
Inhibitory activity tested against inosine-5'-monophosphate dehydrogenase 2 (IMPDH-II) enzyme
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.
Year : 2003
Volume : 13
Issue : 20
First Page : 3557
Last Page : 3560
Authors : Dhar TG, Shen Z, Gu HH, Chen P, Norris D, Watterson SH, Ballentine SK, Fleener CA, Rouleau KA, Barrish JC, Townsend R, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.
|
Inhibitory concentration against Inosine-5'-monophosphate dehydrogenase 2 was determined
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The TosMIC approach to 3-(oxazol-5-yl) indoles: application to the synthesis of indole-based IMPDH inhibitors.
Year : 2002
Volume : 12
Issue : 22
First Page : 3305
Last Page : 3308
Authors : Dhar TG, Shen Z, Fleener CA, Rouleau KA, Barrish JC, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A modified approach to the synthesis of 3-(oxazolyl-5-yl) indoles is reported. This method was applied to the synthesis of series of novel indole based inhibitors of inosine monophosphate dehydrogenase (IMPDH). The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
|
In vitro inhibition of Inosine-5'-monophosphate dehydrogenase 2.
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel guanidine-based inhibitors of inosine monophosphate dehydrogenase.
Year : 2002
Volume : 12
Issue : 20
First Page : 2931
Last Page : 2934
Authors : Iwanowicz EJ, Watterson SH, Liu C, Gu HH, Mitt T, Leftheris K, Barrish JC, Fleener CA, Rouleau K, Sherbina NZ, Hollenbaugh DL.
Abstract : A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
|
Inhibitory activity against human Inosine-5'-monophosphate dehydrogenase 2 (IMPDH type II isoform); Range is 6-10 nM
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.
Year : 1998
Volume : 41
Issue : 4
First Page : 618
Last Page : 622
Authors : Lesiak K, Watanabe KA, Majumdar A, Powell J, Seidman M, Vanderveen K, Goldstein BM, Pankiewicz KW.
Abstract : Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropy-lidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (Ki = 0.3 microM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 microM). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.
|
Inhibitory activity against human Inosine-5'-monophosphate dehydrogenase 2 (IMPDH type II)
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia.
Year : 2002
Volume : 45
Issue : 3
First Page : 703
Last Page : 712
Authors : Pankiewicz KW, Lesiak-Watanabe KB, Watanabe KA, Patterson SE, Jayaram HN, Yalowitz JA, Miller MD, Seidman M, Majumdar A, Prehna G, Goldstein BM.
Abstract : Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.
|
Inhibitory activity against growth of human erythroleukemia K652 cells
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.
Year : 1998
Volume : 41
Issue : 4
First Page : 618
Last Page : 622
Authors : Lesiak K, Watanabe KA, Majumdar A, Powell J, Seidman M, Vanderveen K, Goldstein BM, Pankiewicz KW.
Abstract : Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropy-lidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (Ki = 0.3 microM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 microM). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.
|
Antiproliferative activity against K562 cells
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia.
Year : 2002
Volume : 45
Issue : 3
First Page : 703
Last Page : 712
Authors : Pankiewicz KW, Lesiak-Watanabe KB, Watanabe KA, Patterson SE, Jayaram HN, Yalowitz JA, Miller MD, Seidman M, Majumdar A, Prehna G, Goldstein BM.
Abstract : Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.
|
In vitro antitumor activity against L1210 murine lymphocytic leukemia cells
|
Mus musculus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of heterocyclic analogues of mycophenolic acid as potential chemotherapeutic agents
Year : 1995
Volume : 5
Issue : 8
First Page : 861
Last Page : 866
Authors : Lee J, Anderson WK
|
Inhibitory activity of compound against L1210 leukemia cells in tissue culture
|
Mus musculus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and modeling studies with monocyclic analogues of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 1
First Page : 46
Last Page : 55
Authors : Anderson WK, Boehm TL, Makara GM, Swann RT.
Abstract : Two stepwise procedures, developed for the introduction of the (E)-4-methyl-4-hexenoic acid side chain of mycophenolic acid, were used in the synthesis of monocyclic mycophenolic acid analogues 2a-i. The derivatives with a methyl group or hydrogen at C-4 and lacking the lactone moiety were much less cytotoxic than mycophenolic acid. The monocyclic analogues with a C-4 chloro group did show some activity, albeit much less than mycophenolic acid. The observed differences in potency are rationalized by semiempirical calculations of intramolecular H-bonds.
|
In vitro antitumor activity against MCF-7 human breast adenocarcinoma cells
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of heterocyclic analogues of mycophenolic acid as potential chemotherapeutic agents
Year : 1995
Volume : 5
Issue : 8
First Page : 861
Last Page : 866
Authors : Lee J, Anderson WK
|
Tested for the inhibition of murine PFC response at 12.5 mg/kg dose
|
Mus musculus
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
Tested for the inhibition of murine PFC response at 25 mg/kg dose
|
Mus musculus
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
Tested for the inhibition of murine PFC response at 50 mg/kg dose
|
Mus musculus
|
81.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
Tested for the inhibition of murine PFC response at 6.25 mg/kg dose
|
Mus musculus
|
16.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
Year : 1996
Volume : 39
Issue : 21
First Page : 4181
Last Page : 4196
Authors : Nelson PH, Carr SF, Devens BH, Eugui EM, Franco F, Gonzalez C, Hawley RC, Loughhead DG, Milan DJ, Papp E, Patterson JW, Rouhafza S, Sjogren EB, Smith DB, Stephenson RA, Talamas FX, Waltos AM, Weikert RJ, Wu JC.
Abstract : Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
|
In vivo inhibition of plaque-forming cells in the spleen (PFC/spleen) after 25 mg/kg oral administration in mice.
|
Mus musculus
|
69.0
%
|
|
In vivo inhibition of plaque-forming cells in the spleen (PFC/spleen) after 25 mg/kg oral administration in mice.
|
Mus musculus
|
46.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.
Year : 1990
Volume : 33
Issue : 2
First Page : 833
Last Page : 838
Authors : Nelson PH, Eugui E, Wang CC, Allison AC.
Abstract : The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.
|
In vivo inhibition of plaques per million after 25 mg/kg oral administration in mice.
|
Mus musculus
|
65.0
%
|
|
In vivo inhibition of plaques per million after 25 mg/kg oral administration in mice.
|
Mus musculus
|
44.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.
Year : 1990
Volume : 33
Issue : 2
First Page : 833
Last Page : 838
Authors : Nelson PH, Eugui E, Wang CC, Allison AC.
Abstract : The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.
|
Inhibitory activity against proliferation of peripheral blood mononuclear cells
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolone-based IMPDH inhibitors: introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues.
Year : 2003
Volume : 13
Issue : 3
First Page : 547
Last Page : 551
Authors : Dhar TG, Watterson SH, Chen P, Shen Z, Gu HH, Norris D, Carlsen M, Haslow KD, Pitts WJ, Guo J, Chorba J, Fleener CA, Rouleau KA, Townsend R, Hollenbaugh D, Iwanowicz EJ.
Abstract : The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.
|
In vitro antitumor activity against PSN-1 human pancreatic carcinoma cells
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of heterocyclic analogues of mycophenolic acid as potential chemotherapeutic agents
Year : 1995
Volume : 5
Issue : 8
First Page : 861
Last Page : 866
Authors : Lee J, Anderson WK
|
Inhibitory activity against human T-lymphoblast CEM cell line using T cell proliferation assay
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase.
Year : 2002
Volume : 12
Issue : 16
First Page : 2137
Last Page : 2140
Authors : Pitts WJ, Guo J, Dhar TG, Shen Z, Gu HH, Watterson SH, Bednarz MS, Chen BC, Barrish JC, Bassolino D, Cheney D, Fleener CA, Rouleau KA, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.
|
Inhibitory concentration against human T-lymphoblast CEM cell line (ATCC) by CEM proliferation assay.
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel guanidine-based inhibitors of inosine monophosphate dehydrogenase.
Year : 2002
Volume : 12
Issue : 20
First Page : 2931
Last Page : 2934
Authors : Iwanowicz EJ, Watterson SH, Liu C, Gu HH, Mitt T, Leftheris K, Barrish JC, Fleener CA, Rouleau K, Sherbina NZ, Hollenbaugh DL.
Abstract : A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
|
The human T-lymphoblastCEM cell (ATCC) proliferation inhibitory activity was determined
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel amide-based inhibitors of inosine 5'-monophosphate dehydrogenase.
Year : 2002
Volume : 12
Issue : 20
First Page : 2879
Last Page : 2882
Authors : Watterson SH, Liu C, Dhar TG, Gu HH, Pitts WJ, Barrish JC, Fleener CA, Rouleau K, Sherbina NZ, Hollenbaugh DL, Iwanowicz EJ.
Abstract : A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
|
Inhibition of Rluc-FL-WNV replicon in Vero cells
|
West Nile virus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of compounds with anti-West Nile Virus activity.
Year : 2006
Volume : 49
Issue : 6
First Page : 2127
Last Page : 2137
Authors : Goodell JR, Puig-Basagoiti F, Forshey BM, Shi PY, Ferguson DM.
Abstract : The lack of antiviral compounds targeting flaviviruses represents a significant problem in the development of strategies for treating West Nile Virus (WNV), Dengue, and Yellow Fever infections. Using WNV high-throughput screening techniques developed in our laboratories, we report the identification of several small molecule anti-WNV compounds belonging to four different structural classes including pyrazolines, xanthanes, acridines, and quinolines. The initial set of "hits" was further refined using cell viability-cytotoxicity assays to two 1,3,5-triaryl pyrazoline compounds: 1-(4-chlorophenylacetyl)-5-(4-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole and 1-benzoyl-5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole. On the basis of their activity and favorable therapeutic indexes, these compounds were identified as viable leads and subjected to additional evaluation using an authentic viral titer reduction assay employing an epidemic strain of WNV. The compounds were further evaluated in a transient replicon reporting system to gain insight into the mechanism of action by identifying the step at which inhibition takes place during viral replication. The results indicate the pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets. Progress was also made in understanding the structural requirements for activity by synthesizing a focused chemical library of substituted pyrazolines. Preliminary SAR data are presented that show the aryl-rings are required for activity against WNV. More importantly, the results indicate WNV activity is tolerant to aryl-substitutions paving the way for the design and development of much larger combinatorial libraries with varied physicochemical properties.
|
Inhibition of West Nile virus VLP replicon in BHK21 cell line
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of compounds with anti-West Nile Virus activity.
Year : 2006
Volume : 49
Issue : 6
First Page : 2127
Last Page : 2137
Authors : Goodell JR, Puig-Basagoiti F, Forshey BM, Shi PY, Ferguson DM.
Abstract : The lack of antiviral compounds targeting flaviviruses represents a significant problem in the development of strategies for treating West Nile Virus (WNV), Dengue, and Yellow Fever infections. Using WNV high-throughput screening techniques developed in our laboratories, we report the identification of several small molecule anti-WNV compounds belonging to four different structural classes including pyrazolines, xanthanes, acridines, and quinolines. The initial set of "hits" was further refined using cell viability-cytotoxicity assays to two 1,3,5-triaryl pyrazoline compounds: 1-(4-chlorophenylacetyl)-5-(4-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole and 1-benzoyl-5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole. On the basis of their activity and favorable therapeutic indexes, these compounds were identified as viable leads and subjected to additional evaluation using an authentic viral titer reduction assay employing an epidemic strain of WNV. The compounds were further evaluated in a transient replicon reporting system to gain insight into the mechanism of action by identifying the step at which inhibition takes place during viral replication. The results indicate the pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets. Progress was also made in understanding the structural requirements for activity by synthesizing a focused chemical library of substituted pyrazolines. Preliminary SAR data are presented that show the aryl-rings are required for activity against WNV. More importantly, the results indicate WNV activity is tolerant to aryl-substitutions paving the way for the design and development of much larger combinatorial libraries with varied physicochemical properties.
|
Inhibition of West Nile viral Rluc-Neo-Rep in Vero cells
|
None
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of compounds with anti-West Nile Virus activity.
Year : 2006
Volume : 49
Issue : 6
First Page : 2127
Last Page : 2137
Authors : Goodell JR, Puig-Basagoiti F, Forshey BM, Shi PY, Ferguson DM.
Abstract : The lack of antiviral compounds targeting flaviviruses represents a significant problem in the development of strategies for treating West Nile Virus (WNV), Dengue, and Yellow Fever infections. Using WNV high-throughput screening techniques developed in our laboratories, we report the identification of several small molecule anti-WNV compounds belonging to four different structural classes including pyrazolines, xanthanes, acridines, and quinolines. The initial set of "hits" was further refined using cell viability-cytotoxicity assays to two 1,3,5-triaryl pyrazoline compounds: 1-(4-chlorophenylacetyl)-5-(4-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole and 1-benzoyl-5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole. On the basis of their activity and favorable therapeutic indexes, these compounds were identified as viable leads and subjected to additional evaluation using an authentic viral titer reduction assay employing an epidemic strain of WNV. The compounds were further evaluated in a transient replicon reporting system to gain insight into the mechanism of action by identifying the step at which inhibition takes place during viral replication. The results indicate the pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets. Progress was also made in understanding the structural requirements for activity by synthesizing a focused chemical library of substituted pyrazolines. Preliminary SAR data are presented that show the aryl-rings are required for activity against WNV. More importantly, the results indicate WNV activity is tolerant to aryl-substitutions paving the way for the design and development of much larger combinatorial libraries with varied physicochemical properties.
|
Antiproliferative activity against HUVEC as measured by [3H]thymidine incorporation
|
Homo sapiens
|
99.2
nM
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Antiproliferative activity against Jurkat T cells as measured by [3H]thymidine incorporation
|
Homo sapiens
|
128.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Cell cycle arrest at G1 phase in HUVEC at 1 uM
|
Homo sapiens
|
81.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Cell cycle arrest at S phase in HUVEC at 1 uM
|
Homo sapiens
|
6.5
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Cell cycle arrest at G2/M phase in HUVEC at 1 uM
|
Homo sapiens
|
12.4
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Cell cycle arrest at G1 phase in HUVEC at 1 uM in presence of 50 uM guanosine
|
Homo sapiens
|
71.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Cell cycle arrest at S phase in HUVEC at 1 uM in presence of 50 uM guanosine
|
Homo sapiens
|
11.8
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Cell cycle arrest at G2/M phase in HUVEC at 1 uM in presence of 50 uM guanosine
|
Homo sapiens
|
17.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Antiangiogenic activity in mouse at 60 mg/kg/day, sc
|
Mus musculus
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of type 1 inosine monophosphate dehydrogenase as an antiangiogenic drug target.
Year : 2006
Volume : 49
Issue : 9
First Page : 2677
Last Page : 2680
Authors : Chong CR, Qian DZ, Pan F, Wei Y, Pili R, Sullivan DJ, Liu JO.
Abstract : To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.
|
Inhibition of human IMPDH1
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phosphonic acid-containing analogues of mycophenolic acid as inhibitors of IMPDH.
Year : 2006
Volume : 16
Issue : 13
First Page : 3479
Last Page : 3483
Authors : Watkins WJ, Chen JM, Cho A, Chong L, Collins N, Fardis M, Huang W, Hung M, Kirschberg T, Lee WA, Liu X, Thomas W, Xu J, Zeynalzadegan A, Zhang J.
Abstract : The design, synthesis, and IMPDH inhibitory activity of a series of phosphonic acid-containing analogues of mycophenolic acid are described.
|
Inhibition of human IMPDH2
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phosphonic acid-containing analogues of mycophenolic acid as inhibitors of IMPDH.
Year : 2006
Volume : 16
Issue : 13
First Page : 3479
Last Page : 3483
Authors : Watkins WJ, Chen JM, Cho A, Chong L, Collins N, Fardis M, Huang W, Hung M, Kirschberg T, Lee WA, Liu X, Thomas W, Xu J, Zeynalzadegan A, Zhang J.
Abstract : The design, synthesis, and IMPDH inhibitory activity of a series of phosphonic acid-containing analogues of mycophenolic acid are described.
|
Inhibition of viral RNA levels in HTNV76-118-infected Vero E6 cells at 10 ug/ml
|
Hantaan virus
|
-70.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of ribavirin against Hantaan virus correlates with production of ribavirin-5'-triphosphate, not with inhibition of IMP dehydrogenase.
Year : 2007
Volume : 51
Issue : 1
First Page : 84
Last Page : 88
Authors : Sun Y, Chung DH, Chu YK, Jonsson CB, Parker WB.
Abstract : Ribavirin (RBV) is a broad-spectrum antiviral agent that inhibits the production of infectious Hantaan virus (HTNV). Although the mechanism of action of RBV against HTNV is not understood, RBV is metabolized in human cells to both RBV-5'-monophosphate, which inhibits IMP dehydrogenase, resulting in a decrease in intracellular GTP levels, and RBV-5'-triphosphate (RBV-TP), which could selectively interact with the viral RNA polymerase. To elucidate which activity of RBV was most important to its anti-HTNV activity, the mechanism of action of RBV was studied in Vero E6 cells. Incubation with 10 to 40 mug/ml RBV resulted in a small decrease in GTP levels that was not dose dependent. Increasing the RBV concentration from 10 to 40 mug/ml resulted in a decrease in viral RNA (vRNA) levels and an increase in RBV-TP formation. Mycophenolic acid (MPA), an inhibitor of IMP dehydrogenase, also resulted in a decrease in vRNA levels; however, treatment with MPA resulted in a much greater decrease in GTP levels than that seen with RBV. Treatment with both MPA and RBV resulted in increased reduction of vRNA levels but did not result in enhanced depression of GTP levels. Although guanosine prevented the depression in GTP levels caused by RBV, guanosine only partially prevented the effect of RBV on vRNA levels. These results suggest that the inhibition of IMP dehydrogenase by RBV is of secondary importance to the inhibition of vRNA replication by RBV and that the interaction of RBV-TP with the viral polymerase is the primary action of RBV.
|
Inhibition of CEM cell proliferation
|
Homo sapiens
|
540.0
nM
|
|
Journal : J. Med. Chem.
Title : Acridone-based inhibitors of inosine 5'-monophosphate dehydrogenase: discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419).
Year : 2007
Volume : 50
Issue : 15
First Page : 3730
Last Page : 3742
Authors : Watterson SH, Chen P, Zhao Y, Gu HH, Dhar TG, Xiao Z, Ballentine SK, Shen Z, Fleener CA, Rouleau KA, Obermeier M, Yang Z, McIntyre KW, Shuster DJ, Witmer M, Dambach D, Chao S, Mathur A, Chen BC, Barrish JC, Robl JA, Townsend R, Iwanowicz EJ.
Abstract : Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
|
Inhibition of human IMPDH2
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Acridone-based inhibitors of inosine 5'-monophosphate dehydrogenase: discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419).
Year : 2007
Volume : 50
Issue : 15
First Page : 3730
Last Page : 3742
Authors : Watterson SH, Chen P, Zhao Y, Gu HH, Dhar TG, Xiao Z, Ballentine SK, Shen Z, Fleener CA, Rouleau KA, Obermeier M, Yang Z, McIntyre KW, Shuster DJ, Witmer M, Dambach D, Chao S, Mathur A, Chen BC, Barrish JC, Robl JA, Townsend R, Iwanowicz EJ.
Abstract : Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
|
Inhibition of T cell proliferation in PBMC cells
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Acridone-based inhibitors of inosine 5'-monophosphate dehydrogenase: discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419).
Year : 2007
Volume : 50
Issue : 15
First Page : 3730
Last Page : 3742
Authors : Watterson SH, Chen P, Zhao Y, Gu HH, Dhar TG, Xiao Z, Ballentine SK, Shen Z, Fleener CA, Rouleau KA, Obermeier M, Yang Z, McIntyre KW, Shuster DJ, Witmer M, Dambach D, Chao S, Mathur A, Chen BC, Barrish JC, Robl JA, Townsend R, Iwanowicz EJ.
Abstract : Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
|
Inhibition of [1-14C]sodium acetate uptake at PPARgamma in mouse 3T3-L1 cells at 2 uM
|
Homo sapiens
|
74.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mycophenolic acid as a latent agonist of PPARgamma.
Year : 2007
Volume : 17
Issue : 17
First Page : 4767
Last Page : 4770
Authors : Ubukata M, Takamori H, Ohashi M, Mitsuhashi S, Yamashita K, Asada T, Nakajima N, Matsuura N, Tsuruga M, Taki K, Magae J.
Abstract : Mycophenolic acid (MPA), known as an inhibitor of inosine monophosphate dehydrogenase (IMPDH), was found to inhibit the differentiation of 3T3-L1 pre-adipocytes into mature adipocytes. Although the effect of MPA was attributed to inhibition of IMPDH, we uncovered a hidden biological property of MPA as an agonist of peroxisome proliferator activated receptor gamma (PPARgamma).
|
Inhibition of human IMPDH type 1
|
Homo sapiens
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.
Year : 2007
Volume : 50
Issue : 23
First Page : 5743
Last Page : 5751
Authors : Chen L, Gao G, Felczak K, Bonnac L, Patterson SE, Wilson D, Bennett EM, Jayaram HN, Hedstrom L, Pankiewicz KW.
Abstract : Novel tiazofurin adenine dinucleotide (TAD) analogues 25-33 containing a substituent at C2 of the adenine ring have been synthesized as inhibitors of the two isoforms of human IMP-dehydrogenase. The 2-ethyl TAD analogue 33 [Ki = 1 nM (type I), Ki = 14 nM (type II)] was found to be the most potent. It did not inhibit three other cellular dehydrogenases up to 50 microM. Mycophenolic adenine bis(phosphonate)s containing a 2-phenyl (37) or 2-ethyl group (38), were prepared as metabolically stable compounds, both nanomolar inhibitors. Compound 38 [Ki = 16 nM (type I), Ki = 38 nM (type II)] inhibited proliferation of leukemic K562 cells (IC50 = 1.1 microM) more potently than tiazofurin (IC50 = 12.4 microM) or mycophenolic acid (IC50 = 7.7 microM).
|
Inhibition of human IMPDH type 2
|
Homo sapiens
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.
Year : 2007
Volume : 50
Issue : 23
First Page : 5743
Last Page : 5751
Authors : Chen L, Gao G, Felczak K, Bonnac L, Patterson SE, Wilson D, Bennett EM, Jayaram HN, Hedstrom L, Pankiewicz KW.
Abstract : Novel tiazofurin adenine dinucleotide (TAD) analogues 25-33 containing a substituent at C2 of the adenine ring have been synthesized as inhibitors of the two isoforms of human IMP-dehydrogenase. The 2-ethyl TAD analogue 33 [Ki = 1 nM (type I), Ki = 14 nM (type II)] was found to be the most potent. It did not inhibit three other cellular dehydrogenases up to 50 microM. Mycophenolic adenine bis(phosphonate)s containing a 2-phenyl (37) or 2-ethyl group (38), were prepared as metabolically stable compounds, both nanomolar inhibitors. Compound 38 [Ki = 16 nM (type I), Ki = 38 nM (type II)] inhibited proliferation of leukemic K562 cells (IC50 = 1.1 microM) more potently than tiazofurin (IC50 = 12.4 microM) or mycophenolic acid (IC50 = 7.7 microM).
|
Inhibition of human IMPDH 1
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment.
Year : 2007
Volume : 50
Issue : 26
First Page : 6685
Last Page : 6691
Authors : Chen L, Wilson D, Jayaram HN, Pankiewicz KW.
Abstract : Mycophenolic acid (MPA), an inhibitor of IMP-dehydrogenase (IMPDH), is used worldwide in transplantation. Recently, numerous studies showed its importance in cancer treatment. Consequently, MPA entered clinical trials in advanced multiple myeloma patients. Suberoylanilide hydroxamic acid (SAHA), a potent differentiation agent acting through inhibition of histone deacetylases (HDACs), was recently approved for treatment of cutaneous T cell lymphoma. We report herein the synthesis of dual inhibitors of IMPDH and HDACs. We found that mycophenolic hydroxamic acid (9, MAHA) inhibits both IMPDH (Ki=30 nM) and HDAC (IC50=5.0 microM). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (Ki=1.7 microM) and HDAC (IC50=0.06 microM). Both MAHA (IC50=4.8 microM) and SAHA analogue 14 (IC50=7.7 microM) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.
|
Inhibition of human IMPDH 2
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment.
Year : 2007
Volume : 50
Issue : 26
First Page : 6685
Last Page : 6691
Authors : Chen L, Wilson D, Jayaram HN, Pankiewicz KW.
Abstract : Mycophenolic acid (MPA), an inhibitor of IMP-dehydrogenase (IMPDH), is used worldwide in transplantation. Recently, numerous studies showed its importance in cancer treatment. Consequently, MPA entered clinical trials in advanced multiple myeloma patients. Suberoylanilide hydroxamic acid (SAHA), a potent differentiation agent acting through inhibition of histone deacetylases (HDACs), was recently approved for treatment of cutaneous T cell lymphoma. We report herein the synthesis of dual inhibitors of IMPDH and HDACs. We found that mycophenolic hydroxamic acid (9, MAHA) inhibits both IMPDH (Ki=30 nM) and HDAC (IC50=5.0 microM). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (Ki=1.7 microM) and HDAC (IC50=0.06 microM). Both MAHA (IC50=4.8 microM) and SAHA analogue 14 (IC50=7.7 microM) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.
|
Inhibition of human IMP dehydrogenase 1
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: inhibition of inosine monophosphate dehydrogenase.
Year : 2008
Volume : 16
Issue : 15
First Page : 7462
Last Page : 7469
Authors : Chen L, Petrelli R, Olesiak M, Wilson DJ, Labello NP, Pankiewicz KW.
Abstract : Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (K(i) approximately 0.2 microM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (K(i)=0.3-0.4 microM) than the corresponding parent bis(phosphonate)s 2 and 3 (K(i)=0.04-0.11 microM), respectively.
|
Inhibition of human IMP dehydrogenase 2
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: inhibition of inosine monophosphate dehydrogenase.
Year : 2008
Volume : 16
Issue : 15
First Page : 7462
Last Page : 7469
Authors : Chen L, Petrelli R, Olesiak M, Wilson DJ, Labello NP, Pankiewicz KW.
Abstract : Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (K(i) approximately 0.2 microM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (K(i)=0.3-0.4 microM) than the corresponding parent bis(phosphonate)s 2 and 3 (K(i)=0.04-0.11 microM), respectively.
|
Inhibition of human IMPDH1
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Mycophenolic acid analogs with a modified metabolic profile.
Year : 2008
Volume : 16
Issue : 20
First Page : 9340
Last Page : 9345
Authors : Chen L, Wilson DJ, Labello NP, Jayaram HN, Pankiewicz KW.
Abstract : Mycophenolic acid (MPA), a clinically used immunosuppressant, is extensively metabolized into an inactive C7-glucuronide and removed from circulation. To circumvent the metabolic liability imposed by the C7-hydroxyl group, we have designed a series of hybrid MPA analogs based on the pharmacophores present in MPA and new generations of inosine monophosphate dehydrogenase (IMPDH) inhibitors. The synthesis of MPA analogs has been accomplished by an allylic substitution of a common lactone. Biological evaluations of these analogs and a preliminary structure-activity relationship (SAR) are presented.
|
Inhibition of human IMPDH2
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Mycophenolic acid analogs with a modified metabolic profile.
Year : 2008
Volume : 16
Issue : 20
First Page : 9340
Last Page : 9345
Authors : Chen L, Wilson DJ, Labello NP, Jayaram HN, Pankiewicz KW.
Abstract : Mycophenolic acid (MPA), a clinically used immunosuppressant, is extensively metabolized into an inactive C7-glucuronide and removed from circulation. To circumvent the metabolic liability imposed by the C7-hydroxyl group, we have designed a series of hybrid MPA analogs based on the pharmacophores present in MPA and new generations of inosine monophosphate dehydrogenase (IMPDH) inhibitors. The synthesis of MPA analogs has been accomplished by an allylic substitution of a common lactone. Biological evaluations of these analogs and a preliminary structure-activity relationship (SAR) are presented.
|
Antiviral activity against Respiratory syncytial virus A2 infected in Vero-76 cells after 5 days by plaque reduction assay
|
Respiratory syncytial virus
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiviral and cytotoxic activities of aminoarylazo compounds and aryltriazene derivatives.
Year : 2009
Volume : 17
Issue : 13
First Page : 4425
Last Page : 4440
Authors : Tonelli M, Vazzana I, Tasso B, Boido V, Sparatore F, Fermeglia M, Paneni MS, Posocco P, Pricl S, La Colla P, Ibba C, Secci B, Collu G, Loddo R.
Abstract : Twelve aminoarylazocompounds (A-C) and 46 aryltriazene 7 derivatives (D-G) have been synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. Eight aminoazocompounds and 27 aryltriazene derivatives exhibited antiviral activity, sometimes of high level, against one or more viruses. A marked activity against BVDV and YFV was prevailing among the former compounds, while the latter type of compounds affected mainly CVB-2 and RSV. None of the active compounds inhibited the multiplication of HIV-1, VSV and VV. Arranged in order of decreasing potency and selectivity versus the host cell lines, the best compounds are the following; BVDV: 1>7>8>4; YFV: 7>5; CVB-2: 25>56>18; RSV: 14>20>55>38>18>19; HSV-1: 2. For these compounds the EC(50) ranged from 1.6 microM (1) to 12 microM (18), and the S. I. from 19.4 (1) to 4.2 (2). Thus the aminoarylazo and aryltriazene substructures appear as interesting molecular component for developing antiviral agents against ss RNA viruses, particularly against RSV and BVDV, which are important human and veterinary pathogens. Finally, molecular modeling investigations indicated that compounds of structure A-C, active against BVDV, could work targeting the viral RNA-dependent RNA-polymerase (RdRp), having been observed a good agreement between the trends of the estimated IC(50) and the experimental EC(50) values.
|
Inhibition of Dengue virus IMPDH
|
Dengue virus
|
0.1
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : The medicinal chemistry of dengue fever.
Year : 2009
Volume : 52
Issue : 24
First Page : 7911
Last Page : 7926
Authors : Stevens AJ, Gahan ME, Mahalingam S, Keller PA.
|
Antiviral activity against RSV A2 infected in african green monkey Vero cells after 5 days by plaque reduction assay
|
Respiratory syncytial virus
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiviral activity of benzimidazole derivatives. II. Antiviral activity of 2-phenylbenzimidazole derivatives.
Year : 2010
Volume : 18
Issue : 8
First Page : 2937
Last Page : 2953
Authors : Tonelli M, Simone M, Tasso B, Novelli F, Boido V, Sparatore F, Paglietti G, Pricl S, Giliberti G, Blois S, Ibba C, Sanna G, Loddo R, La Colla P.
Abstract : Seventy-six 2-phenylbenzimidazole derivatives were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, BVDV, Sb-1, HSV-1, and YFV, while HIV-1 and VSV were not affected, and RSV, VV and Reo-1 were only susceptible to a few compounds. Thirty-nine compounds exhibited high activity (EC(50)=0.1-10microM) against at least one virus, and four of them were outstanding for their high and selective activity against VV (24, EC(50)=0.1microM) and BVDV (50, 51, and 53 with EC(50)=1.5, 0.8, and 1.0microM, respectively). The last compounds inhibited at low micromolar concentrations the NS5B RdRp of BVDV and also of HCV, the latter sharing structural similarity with the former. The considered compounds represent attractive leads for the development of antiviral agents against poxviruses, pestiviruses and even HCV, which are important human and veterinary pathogens.
|
Inhibition of Aspergillus fumigatus-mediated dendritic cell maturation assessed as decreased CD86 expression at 10 uM
|
None
|
43.8
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Impact of mycophenolic acid on the functionality of human polymorphonuclear neutrophils and dendritic cells during interaction with Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 7
First Page : 2644
Last Page : 2646
Authors : Mezger M, Wozniok I, Blockhaus C, Kurzai O, Hebart H, Einsele H, Loeffler J.
Abstract : Mycophenolic acid (MPA) is used clinically to prevent graft rejection but may increase the risk of fungal infection. We observed that MPA enhanced the Aspergillus fumigatus-induced oxidative burst of polymorphonuclear neutrophils, but without a corresponding increase in fungal killing. Furthermore, MPA inhibited the proinflammatory cytokine response and maturation of dendritic cells.
|
Inhibition of Aspergillus fumigatus-mediated dendritic cell maturation assessed as decreased CD83 expression at 10 uM
|
None
|
21.1
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Impact of mycophenolic acid on the functionality of human polymorphonuclear neutrophils and dendritic cells during interaction with Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 7
First Page : 2644
Last Page : 2646
Authors : Mezger M, Wozniok I, Blockhaus C, Kurzai O, Hebart H, Einsele H, Loeffler J.
Abstract : Mycophenolic acid (MPA) is used clinically to prevent graft rejection but may increase the risk of fungal infection. We observed that MPA enhanced the Aspergillus fumigatus-induced oxidative burst of polymorphonuclear neutrophils, but without a corresponding increase in fungal killing. Furthermore, MPA inhibited the proinflammatory cytokine response and maturation of dendritic cells.
|
Inhibition of Aspergillus fumigatus-mediated dendritic cell maturation assessed as decreased CD40 expression at 10 uM
|
None
|
39.3
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Impact of mycophenolic acid on the functionality of human polymorphonuclear neutrophils and dendritic cells during interaction with Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 7
First Page : 2644
Last Page : 2646
Authors : Mezger M, Wozniok I, Blockhaus C, Kurzai O, Hebart H, Einsele H, Loeffler J.
Abstract : Mycophenolic acid (MPA) is used clinically to prevent graft rejection but may increase the risk of fungal infection. We observed that MPA enhanced the Aspergillus fumigatus-induced oxidative burst of polymorphonuclear neutrophils, but without a corresponding increase in fungal killing. Furthermore, MPA inhibited the proinflammatory cytokine response and maturation of dendritic cells.
|
Inhibition of Aspergillus fumigatus-mediated dendritic cell maturation assessed as decreased CD1a expression at 10 uM
|
None
|
68.8
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Impact of mycophenolic acid on the functionality of human polymorphonuclear neutrophils and dendritic cells during interaction with Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 7
First Page : 2644
Last Page : 2646
Authors : Mezger M, Wozniok I, Blockhaus C, Kurzai O, Hebart H, Einsele H, Loeffler J.
Abstract : Mycophenolic acid (MPA) is used clinically to prevent graft rejection but may increase the risk of fungal infection. We observed that MPA enhanced the Aspergillus fumigatus-induced oxidative burst of polymorphonuclear neutrophils, but without a corresponding increase in fungal killing. Furthermore, MPA inhibited the proinflammatory cytokine response and maturation of dendritic cells.
|
Inhibition of Aspergillus fumigatus-mediated dendritic cell maturation assessed as decreased CD80 expression at 10 uM
|
None
|
46.7
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Impact of mycophenolic acid on the functionality of human polymorphonuclear neutrophils and dendritic cells during interaction with Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 7
First Page : 2644
Last Page : 2646
Authors : Mezger M, Wozniok I, Blockhaus C, Kurzai O, Hebart H, Einsele H, Loeffler J.
Abstract : Mycophenolic acid (MPA) is used clinically to prevent graft rejection but may increase the risk of fungal infection. We observed that MPA enhanced the Aspergillus fumigatus-induced oxidative burst of polymorphonuclear neutrophils, but without a corresponding increase in fungal killing. Furthermore, MPA inhibited the proinflammatory cytokine response and maturation of dendritic cells.
|
Inhibition of human IMPDH1 expressed in Escherichia coli strain BL21(DE3) after 60 mins
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase and differentiation induction of K562 cells among the mycophenolic acid derivatives.
Year : 2010
Volume : 18
Issue : 22
First Page : 8106
Last Page : 8111
Authors : Mitsuhashi S, Takenaka J, Iwamori K, Nakajima N, Ubukata M.
Abstract : Inosine monophosphate dehydrogenases (IMPDHs) are the committed step in de novo guanine nucleotide biosynthesis. There are two separate, but very closely related IMPDH isoenzymes, termed type I and type II. IMPDHs are widely believed to be major targets for cancer and transplantation therapy. Mycophenolic acid (MPA) is a potent inhibitor of IMPDHs. Previously, we found that MPA acted as a latent agonist of this nuclear hormone receptor in U2OS cells, and 6'-hydroxamic acid derivatives of MPA inhibited tubulin-specific histone deacetylase[s] (HDAC[s]) in HeLa cells. Although MPA is a promising lead compound, structure-activity relationships (SARs) for inhibition of IMPDH, and the mechanism action of MPA derivatives have not well been understood. We therefore synthesized, evaluated MPA derivatives as IMPDH inhibitor in vitro and cellular level, and explored their biological function and mechanism in cultured cells. This paper exhibits that (i) functional groups at C-5, C-7, and C-6' positions in MPA are important for inhibitory activity against IMPDH, (ii) it is difficult to improve specificity against IMPDH II by modification of 5-, 7-, and 6'-group, (iii) demethylation of 5-OMe results in increasing hydrophilicity, and lowering cell permeability, (iv) ester bonds of protective groups at C-7 and C-6' positions are hydrolyzed to give MPA in cultures, (v) the effects of a tubulin-specific HDAC[s] inhibitor on proliferation and differentiation are weaker than its inhibitory activity against IMPDH. The present work may provide insight into the development of a new class of drug lead for treating cancer and transplantation.
|
Inhibition of human IMPDH2 expressed in Escherichia coli strain BL21(DE3) after 60 mins
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase and differentiation induction of K562 cells among the mycophenolic acid derivatives.
Year : 2010
Volume : 18
Issue : 22
First Page : 8106
Last Page : 8111
Authors : Mitsuhashi S, Takenaka J, Iwamori K, Nakajima N, Ubukata M.
Abstract : Inosine monophosphate dehydrogenases (IMPDHs) are the committed step in de novo guanine nucleotide biosynthesis. There are two separate, but very closely related IMPDH isoenzymes, termed type I and type II. IMPDHs are widely believed to be major targets for cancer and transplantation therapy. Mycophenolic acid (MPA) is a potent inhibitor of IMPDHs. Previously, we found that MPA acted as a latent agonist of this nuclear hormone receptor in U2OS cells, and 6'-hydroxamic acid derivatives of MPA inhibited tubulin-specific histone deacetylase[s] (HDAC[s]) in HeLa cells. Although MPA is a promising lead compound, structure-activity relationships (SARs) for inhibition of IMPDH, and the mechanism action of MPA derivatives have not well been understood. We therefore synthesized, evaluated MPA derivatives as IMPDH inhibitor in vitro and cellular level, and explored their biological function and mechanism in cultured cells. This paper exhibits that (i) functional groups at C-5, C-7, and C-6' positions in MPA are important for inhibitory activity against IMPDH, (ii) it is difficult to improve specificity against IMPDH II by modification of 5-, 7-, and 6'-group, (iii) demethylation of 5-OMe results in increasing hydrophilicity, and lowering cell permeability, (iv) ester bonds of protective groups at C-7 and C-6' positions are hydrolyzed to give MPA in cultures, (v) the effects of a tubulin-specific HDAC[s] inhibitor on proliferation and differentiation are weaker than its inhibitory activity against IMPDH. The present work may provide insight into the development of a new class of drug lead for treating cancer and transplantation.
|
Cytotoxicity against human K562 cells after 72 hrs by trypan blue exclusion assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase and differentiation induction of K562 cells among the mycophenolic acid derivatives.
Year : 2010
Volume : 18
Issue : 22
First Page : 8106
Last Page : 8111
Authors : Mitsuhashi S, Takenaka J, Iwamori K, Nakajima N, Ubukata M.
Abstract : Inosine monophosphate dehydrogenases (IMPDHs) are the committed step in de novo guanine nucleotide biosynthesis. There are two separate, but very closely related IMPDH isoenzymes, termed type I and type II. IMPDHs are widely believed to be major targets for cancer and transplantation therapy. Mycophenolic acid (MPA) is a potent inhibitor of IMPDHs. Previously, we found that MPA acted as a latent agonist of this nuclear hormone receptor in U2OS cells, and 6'-hydroxamic acid derivatives of MPA inhibited tubulin-specific histone deacetylase[s] (HDAC[s]) in HeLa cells. Although MPA is a promising lead compound, structure-activity relationships (SARs) for inhibition of IMPDH, and the mechanism action of MPA derivatives have not well been understood. We therefore synthesized, evaluated MPA derivatives as IMPDH inhibitor in vitro and cellular level, and explored their biological function and mechanism in cultured cells. This paper exhibits that (i) functional groups at C-5, C-7, and C-6' positions in MPA are important for inhibitory activity against IMPDH, (ii) it is difficult to improve specificity against IMPDH II by modification of 5-, 7-, and 6'-group, (iii) demethylation of 5-OMe results in increasing hydrophilicity, and lowering cell permeability, (iv) ester bonds of protective groups at C-7 and C-6' positions are hydrolyzed to give MPA in cultures, (v) the effects of a tubulin-specific HDAC[s] inhibitor on proliferation and differentiation are weaker than its inhibitory activity against IMPDH. The present work may provide insight into the development of a new class of drug lead for treating cancer and transplantation.
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Response HTS to Identify Inhibitors of 5'UTR Stem-Loop Driven Prion Protein mRNA Translation in H4 Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1827 (Project Summary), 1813 (Primary HTS)]
|
None
|
116.0
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of human IMPDH2 by Spectrophotometer
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain.
Year : 2011
Volume : 19
Issue : 5
First Page : 1594
Last Page : 1605
Authors : Felczak K, Chen L, Wilson D, Williams J, Vince R, Petrelli R, Jayaram HN, Kusumanchi P, Kumar M, Pankiewicz KW.
Abstract : Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K(i)=5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC(50)=0.45 μM). Compound 4 was as potent as Gleevec (IC(50)=0.56 μM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K(i)'s lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH.
|
Inhibition of human IMPDH1 by Spectrophotometry
|
Homo sapiens
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain.
Year : 2011
Volume : 19
Issue : 5
First Page : 1594
Last Page : 1605
Authors : Felczak K, Chen L, Wilson D, Williams J, Vince R, Petrelli R, Jayaram HN, Kusumanchi P, Kumar M, Pankiewicz KW.
Abstract : Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K(i)=5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC(50)=0.45 μM). Compound 4 was as potent as Gleevec (IC(50)=0.56 μM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K(i)'s lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH.
|
PUBCHEM_BIOASSAY: A Cell-Based Confirmatory Screen for Compounds that Inhibit VEEV, TC-83. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID588723]
|
Chlorocebus sabaeus
|
50.0
nM
|
|
Title : PubChem BioAssay data set
|
Immunosuppressive activity in in mouse T-cells assessed as inhibition of concanavalin A-induced proliferation
|
Mus musculus
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The design, synthesis and in vitro immunosuppressive evaluation of novel isobenzofuran derivatives.
Year : 2012
Volume : 22
Issue : 1
First Page : 53
Last Page : 56
Authors : Yang N, Wang QH, Wang WQ, Wang J, Li F, Tan SP, Cheng MS.
Abstract : The synthesis and biological evaluation of a series of novel isobenzofuran-based compounds are described. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and IMPDH type II inhibitor activity in vitro, as well as their structure-activity relationships were assessed. Several compounds demonstrated highly efficacious immunosuppressive properties, especially compounds 2d, 2e, 2h and 2j, which were superior to MPA, while compounds 2k, 2m, 2n, 4c and 5d exhibited an equipotent inhibitory activity compared to MPA. Generally, it was obviously demonstrated that α,β-unsaturated amides proved more potent than the diamide and urea series. The present study provides a guide for further research on development of safe and effective immunosuppressive agents.
|
Inhibition of IMPDH2 using inosine 5'-monophosphate as substrate by spectrophotometry
|
None
|
630.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Penicacids A-C, three new mycophenolic acid derivatives and immunosuppressive activities from the marine-derived fungus Penicillium sp. SOF07.
Year : 2012
Volume : 22
Issue : 9
First Page : 3332
Last Page : 3335
Authors : Chen Z, Zheng Z, Huang H, Song Y, Zhang X, Ma J, Wang B, Zhang C, Ju J.
Abstract : Three new mycophenolic acid derivatives, penicacids A-C (1-3), together with two known analogues, mycophenolic acid (MPA, 4) and 4'-hydroxy-MPA (5), were isolated from a fungus Penicillium sp. SOF07 derived from a South China Sea marine sediment. The structures of compounds 1-3 were elucidated on the basis of MS and NMR ((1)H, (13)C, HSQC and HMBC) data analyses and comparisons with the known compounds. Structure-activity relationship studies of compounds 1-5 focused on inosine-monophosphate dehydrogenase inhibition revealed that hydroxylation at C-4', methylation at C-7-OH, dual hydroxylation at C-2'/C-3' double bond of MPA diminished bioactivity whereas glucosyl hydroxylation at C-4' correlated to bioactivity comparable to that observed for MPA.
|
Immunosuppressive activity in C57BL/6 mouse T lymphocytes assessed as inhibition of cell proliferation after 72 hrs by MTT assay
|
Mus musculus
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Penicacids A-C, three new mycophenolic acid derivatives and immunosuppressive activities from the marine-derived fungus Penicillium sp. SOF07.
Year : 2012
Volume : 22
Issue : 9
First Page : 3332
Last Page : 3335
Authors : Chen Z, Zheng Z, Huang H, Song Y, Zhang X, Ma J, Wang B, Zhang C, Ju J.
Abstract : Three new mycophenolic acid derivatives, penicacids A-C (1-3), together with two known analogues, mycophenolic acid (MPA, 4) and 4'-hydroxy-MPA (5), were isolated from a fungus Penicillium sp. SOF07 derived from a South China Sea marine sediment. The structures of compounds 1-3 were elucidated on the basis of MS and NMR ((1)H, (13)C, HSQC and HMBC) data analyses and comparisons with the known compounds. Structure-activity relationship studies of compounds 1-5 focused on inosine-monophosphate dehydrogenase inhibition revealed that hydroxylation at C-4', methylation at C-7-OH, dual hydroxylation at C-2'/C-3' double bond of MPA diminished bioactivity whereas glucosyl hydroxylation at C-4' correlated to bioactivity comparable to that observed for MPA.
|
Antiproliferative activity against human Jurkat cells after 48 hrs by MTT assay
|
Homo sapiens
|
193.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of novel mycophenolic acid conjugates containing nitro-acridine/acridone derivatives.
Year : 2012
Volume : 54
First Page : 197
Last Page : 201
Authors : Malachowska-Ugarte M, Cholewinski G, Dzierzbicka K, Trzonkowski P.
Abstract : Hybrid pharmacophore anti-proliferative compounds, comprised of mycophenolic acid (MPA) and 1-nitroacridine/4-nitroacridone derivative have been synthesized and evaluated as inhibitors of five different leukemia cell lines (Jurkat, Molt-4, HL-60, CCRF-CEM, L1210) and human peripheral blood mononuclear cells from healthy donors. These conjugates possess different length of the linker between MPA and heterocyclic units. The type of heterocyclic part influenced their cytotoxic and anti-proliferative properties. Coupling of MPA 1 with 9-(ω-aminoalkyl)amino-1-nitroacridines 2 and 1-[(ω-aminoalkyl)-4-nitro-9(10H)]-acridones 3 was tested. Although all tested conjugates were active, compounds 4a-e exhibited the highest potency. Preliminary experiments with GMP suggested that the tested compounds acted as IMPDH inhibitors.
|
Antiproliferative activity against human MOLT4 cells after 48 hrs by MTT assay
|
Homo sapiens
|
75.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of novel mycophenolic acid conjugates containing nitro-acridine/acridone derivatives.
Year : 2012
Volume : 54
First Page : 197
Last Page : 201
Authors : Malachowska-Ugarte M, Cholewinski G, Dzierzbicka K, Trzonkowski P.
Abstract : Hybrid pharmacophore anti-proliferative compounds, comprised of mycophenolic acid (MPA) and 1-nitroacridine/4-nitroacridone derivative have been synthesized and evaluated as inhibitors of five different leukemia cell lines (Jurkat, Molt-4, HL-60, CCRF-CEM, L1210) and human peripheral blood mononuclear cells from healthy donors. These conjugates possess different length of the linker between MPA and heterocyclic units. The type of heterocyclic part influenced their cytotoxic and anti-proliferative properties. Coupling of MPA 1 with 9-(ω-aminoalkyl)amino-1-nitroacridines 2 and 1-[(ω-aminoalkyl)-4-nitro-9(10H)]-acridones 3 was tested. Although all tested conjugates were active, compounds 4a-e exhibited the highest potency. Preliminary experiments with GMP suggested that the tested compounds acted as IMPDH inhibitors.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
-6.25
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
-7.04
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Antiviral activity against Dengue virus 2 infected in BHK-D2RepT cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter replicon-based assay
|
Dengue virus 2
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping.
Year : 2012
Volume : 55
Issue : 14
First Page : 6278
Last Page : 6293
Authors : Deng J, Li N, Liu H, Zuo Z, Liew OW, Xu W, Chen G, Tong X, Tang W, Zhu J, Zuo J, Jiang H, Yang CG, Li J, Zhu W.
Abstract : By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC(50) = 13.12 ± 1.03 μM). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC(50) values of 7.46 ± 1.15 to 48.59 ± 3.46 μM, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV.
|
Inhibition of HDAC in human K562 cells using Boc-Lys[Ac]-AMC as substrate at 10 uM incubated for 10 mins prior to substrate addition measured after 80 mins by fluorescence assay
|
Homo sapiens
|
3.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH.
Year : 2013
Volume : 23
Issue : 18
First Page : 5140
Last Page : 5144
Authors : Sunohara K, Mitsuhashi S, Shigetomi K, Ubukata M.
Abstract : Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type I and II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 μM. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC.
|
Cytotoxicity against human PBMC after 72 hrs by MTT assay
|
Homo sapiens
|
44.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of mycophenolic acid-amino acid derivatives.
Year : 2013
Volume : 69
First Page : 863
Last Page : 871
Authors : Iwaszkiewicz-Grzes D, Cholewinski G, Kot-Wasik A, Trzonkowski P, Dzierzbicka K.
Abstract : In search of new immunosuppressants we synthesized 11 amino acids derivatives of MPA as methyl esters 10a-k using EDCI/DMAP and their corresponding amino acid derivatives in free acid form 11a-k by hydrolysis of ester group with LiOH/MeOH. New analogs were evaluated as growth inhibitors of lymphoid cell line (Jurkat) and human peripheral blood mononuclear cells (PBMC) from healthy donors. According to obtained results recovering of free carboxylic group increased their activity. Additionally, the cytotoxic properties depends on the substituent and configuration at chiral center in amino acid unit. The compounds 10j, 11e and 11h exhibited higher potency than MPA 1 in vitro.
|
Antiproliferative activity against human PBMC assessed as incorporation of [3H]thymidine after 18 hrs by scintillation counting analysis
|
Homo sapiens
|
0.06
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of mycophenolic acid-amino acid derivatives.
Year : 2013
Volume : 69
First Page : 863
Last Page : 871
Authors : Iwaszkiewicz-Grzes D, Cholewinski G, Kot-Wasik A, Trzonkowski P, Dzierzbicka K.
Abstract : In search of new immunosuppressants we synthesized 11 amino acids derivatives of MPA as methyl esters 10a-k using EDCI/DMAP and their corresponding amino acid derivatives in free acid form 11a-k by hydrolysis of ester group with LiOH/MeOH. New analogs were evaluated as growth inhibitors of lymphoid cell line (Jurkat) and human peripheral blood mononuclear cells (PBMC) from healthy donors. According to obtained results recovering of free carboxylic group increased their activity. Additionally, the cytotoxic properties depends on the substituent and configuration at chiral center in amino acid unit. The compounds 10j, 11e and 11h exhibited higher potency than MPA 1 in vitro.
|
Inhibition of human IMPDH
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of mycophenolic acid-amino acid derivatives.
Year : 2013
Volume : 69
First Page : 863
Last Page : 871
Authors : Iwaszkiewicz-Grzes D, Cholewinski G, Kot-Wasik A, Trzonkowski P, Dzierzbicka K.
Abstract : In search of new immunosuppressants we synthesized 11 amino acids derivatives of MPA as methyl esters 10a-k using EDCI/DMAP and their corresponding amino acid derivatives in free acid form 11a-k by hydrolysis of ester group with LiOH/MeOH. New analogs were evaluated as growth inhibitors of lymphoid cell line (Jurkat) and human peripheral blood mononuclear cells (PBMC) from healthy donors. According to obtained results recovering of free carboxylic group increased their activity. Additionally, the cytotoxic properties depends on the substituent and configuration at chiral center in amino acid unit. The compounds 10j, 11e and 11h exhibited higher potency than MPA 1 in vitro.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
106.79
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
100.09
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Binding affinity to human IMPDH
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : NAD-based inhibitors with anticancer potential.
Year : 2014
Volume : 24
Issue : 1
First Page : 332
Last Page : 336
Authors : Felczak K, Vince R, Pankiewicz KW.
Abstract : Three classes of novel inhibitors of inosine monophosphate dehydrogenase have been prepared and their anti-proliferative properties were evaluated against several cancer cell lines. (1) Mycophenolic adenine dinucleotide analogues (8-13) containing a substituent at the C2 of adenine ring were found to be potent inhibitors of IMPDH (Ki's in range of 0.6-82nM) and sub-μM inhibitors of leukemic K562 cell proliferation. (2) Mycophenolic adenosine (d and l) esters (20 and 21) showed a potent inhibition of IMPDH2 (Ki=102 and Ki=231nM, respectively) and inhibition of K562 cell growth (IC50=0.5 and IC50=1.6μM). These compounds serve both as inhibitors of the enzyme and as a depot form of mycophenolic acid. The corresponding amide analogue 22, also a potent inhibitor of IMPDH (Ki=84nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)- and (d)-valine adenine di-amide derivatives 25 (Ki=9nM) and 28 (Ki=3nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells.
|
Inhibition of Chikungunya virus IMPDH
|
Chikungunya virus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Chikungunya virus: emerging targets and new opportunities for medicinal chemistry.
Year : 2014
Volume : 57
Issue : 4
First Page : 1147
Last Page : 1166
Authors : Rashad AA, Mahalingam S, Keller PA.
Abstract : Chikungunya virus is an emerging arbovirus that is widespread in tropical regions and is spreading quickly to temperate climates with recent epidemics in Africa and Asia and documented outbreaks in Europe and the Americas. It is having an increasingly major impact on humankind, with potentially life-threatening and debilitating arthritis. There is no treatment available, and only in the past 24 months have lead compounds for development as potential therapeutics been reported. This Perspective discusses the chikungunya virus as a significant, new emerging topic for medicinal chemistry, highlighting the key viral target proteins and their molecular functions that can be used in drug design, as well as the most important ongoing developments for anti-chikungunya virus research. It represents a complete picture of the current medicinal chemistry of chikungunya, supporting the development of chemotherapeutics through drug discovery and design targeting this virus.
|
Immunosuppressive activity in anti-CD3/anti-CD28-induced human PBMC after 96 hrs by flow cytometry
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Nat. Prod.
Title : Nitrogen-containing dihydro-β-agarofuran derivatives from Tripterygium wilfordii.
Year : 2014
Volume : 77
Issue : 7
First Page : 1650
Last Page : 1657
Authors : Luo Y, Pu X, Luo G, Zhou M, Ye Q, Liu Y, Gu J, Qi H, Li G, Zhang G.
Abstract : Thunder god vine, the dried roots of Tripterygium wilfordii, is a widely used traditional Chinese medicine. More than 200 bioactive complex natural products have been isolated from this herb. Inspired by the diversity of chemical structures and bioactivities of the components of this herb, the investigation to mine new chemical entities as potential drug leads led to the identification of 36 nitrogen-containing compounds. Among them, 18 new dihydro-β-agarofuran alkaloids (tripterygiumines A-L (1-12), M-Q (22-26), and R (33)) were identified from the spectroscopic data and chemical degradation studies. Tripterygiumine Q (26) exhibited immunosuppressive activity against human peripheral mononuclear cells with an IC50 value of 8.67 μM and showed no cytotoxicity, even at 100 μM, indicating that 26 may represent a novel scaffold for the development of new immunosuppressants.
|
Antiviral activity against Respiratory syncytial virus infected in african green monkey Vero 76 cells assessed as reduction in plaque number after 5 days by plaque reduction assay
|
Respiratory syncytial virus
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiviral activity of benzimidazole derivatives. III. Novel anti-CVB-5, anti-RSV and anti-Sb-1 agents.
Year : 2014
Volume : 22
Issue : 17
First Page : 4893
Last Page : 4909
Authors : Tonelli M, Novelli F, Tasso B, Vazzana I, Sparatore A, Boido V, Sparatore F, La Colla P, Sanna G, Giliberti G, Busonera B, Farci P, Ibba C, Loddo R.
Abstract : A library of eighty-six assorted benzimidazole derivatives was screened for antiviral activity against a panel of ten RNA and DNA viruses. Fifty-two of them displayed different levels of activity against one or more viruses, among which CVB-5, RSV, BVDV and Sb-1 were the most frequently affected. In particular, fourteen compounds exhibited an EC50 in the range 9-17μM (SI from 6 to >11) versus CVB-5, and seven compounds showed an EC50 in the range 5-15μM (SI from 6.7 to ⩾20) against RSV, thus resulting comparable to or more potent than the respective reference drugs (NM108 and ribavirin). Most of these compounds derive from 2-benzylbenzimidazole, but also other molecular scaffolds [as 1-phenylbenzimidazole (2), 2-trifluoromethylbenzimidazole (69), dihydropyrido[3',2':4,5]imidazo[1,2-a][1,4]benzodiazepin-5-one (3), dibenzo[c,e]benzimidazo[1,2-a]azepine (22), and 2-(tetrahydropyran-2-yl)benzimidazole (81, 82 and 86)] are related to interesting levels of activity against these or other viruses (BVDV, Sb-1). Thus, these scaffolds (some of which, so far unexplored), represent valid starting points to develop more efficient agents against pathologies caused by CVB-5, RSV, BVDV and Sb-1 viruses.
|
Antiviral activity against human RSV infected in african green monkey Vero76 cells assessed as inhibition of virus-induced cytopathogenicity after 5 days by plaque reduction assay
|
Human respiratory syncytial virus
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiviral activity of benzotriazole derivatives. 5-[4-(Benzotriazol-2-yl)phenoxy]-2,2-dimethylpentanoic acids potently and selectively inhibit Coxsackie Virus B5.
Year : 2015
Volume : 23
Issue : 21
First Page : 7024
Last Page : 7034
Authors : Loddo R, Novelli F, Sparatore A, Tasso B, Tonelli M, Boido V, Sparatore F, Collu G, Delogu I, Giliberti G, La Colla P.
Abstract : A library of 64 benzotriazole derivatives (17 of which were [4-(benzotriazol-2-yl)phenoxy]alkanoic acids) were screened for antiviral activity against a panel of twelve DNA and RNA viruses. Twenty-six compounds (12 of which were [4-(benzotriazol-2-yl)phenoxy]alkanoic acids) displayed activity against one or more viruses. CVB-5, RSV, BVDV, Sb-1 and YFV were, in decreasing order, the more frequently and effectively affected viruses; DENV-2, WNV, HIV-1 and Reo-1 were only occasionally and modestly affected, while the remaining viruses were not affected by any of the tested compounds. Worth of note were compounds 33 and 35; the former for the activity against Sb-1 (EC50=7 μM) and the latter for the large spectrum of activity including six viruses with a mean EC50=12 μM. Even more interesting were the alkanoic acids 45-48 and 50-57 for their activity against RSV and/or CVB-5. In particular, compound 56 displayed a potent and selective activity against CVB-5 with EC50=0.15 μM and SI=100, thus representing a valuable hit compound for the development of antiviral agents for the treatment of human pathologies related to this virus.
|
Antiviral activity against Para-influenza-3 virus infected in African green monkey Vero cells assessed as protection against virus-induced cytopathic effect measured after 3 to 5 days by microscopic analysis
|
Human parainfluenza virus 3
|
800.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and in vitro antiviral evaluation of 4-substituted 3,4-dihydropyrimidinones.
Year : 2017
Volume : 27
Issue : 2
First Page : 139
Last Page : 142
Authors : Kumarasamy D, Roy BG, Rocha-Pereira J, Neyts J, Nanjappan S, Maity S, Mookerjee M, Naesens L.
Abstract : A series of 4-substituted 3,4-dihydropyrimidine-2-ones (DHPM) was synthesized, characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The compounds were evaluated in vitro for their antiviral activity against a broad range of DNA and RNA viruses, along with assessment for potential cytotoxicity in diverse mammalian cell lines. Compound 4m, which possesses a long lipophilic side chain, was found to be a potent and selective inhibitor of Punta Toro virus, a member of the Bunyaviridae. For Rift Valley fever virus, which is another Bunyavirus, the activity of 4m was negligible. DHPMs with a C-4 aryl moiety bearing halogen substitution (4b, 4c and 4d) were found to be cytotoxic in MT4 cells.
|
Antiviral activity against para influenza 3 virus infected in African green monkey Vero cells assessed as inhibition of viral-induced cytopathic effect measured after 3 to 6 days post infection by microscopic analysis
|
Human parainfluenza virus 3
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.
Year : 2017
Volume : 135
First Page : 467
Last Page : 478
Authors : Tonelli M, Naesens L, Gazzarrini S, Santucci M, Cichero E, Tasso B, Moroni A, Costi MP, Loddo R.
Abstract : We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC50 = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC50 ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC50 = 5.8 μM, SI > 43).
|
Antiviral activity against Parainfluenza virus 3 infected in human HeLa cells assessed as inhibition of virus-induced cytopathicity
|
Human parainfluenza virus 3
|
400.0
nM
|
|
Journal : Bioorg Med Chem
Title : Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs.
Year : 2018
Volume : 26
Issue : 12
First Page : 3596
Last Page : 3609
Authors : Pileggi E, Serpi M, Andrei G, Schols D, Snoeck R, Pertusati F.
Abstract : The importance of phosphonoamidate prodrugs (ProTides) of acyclic nucleoside phosphonate (ANPs) is highlighted by the approval of Tenofovir Alafenamide Fumarate for the treatment of HIV and HBV infections. In the present paper we are reporting an expedient, one-pot, two-steps synthesis of allyl phosphonoamidates and diamidates that offers a time saving strategy when compared to literature methods. The use of these substrates in the cross metathesis reactions with alkenyl functionalised thymine and uracil nucleobases is reported. ANPs prodrugs synthesized via this methodology were evaluated for their antiviral activities against DNA and RNA viruses. It is anticipated that the use of 5,6,7,8-tetrahydro-1-napthyl as aryloxy moiety is capable to confer antiviral activity among a series of otherwise inactive uracil ProTides.
|
Antichlamydial activity against Chlamydia pneumoniae K7 infected in HL cells assessed as chlamydial inhibition at 50 uM after 70 hrs by fluorescent microscopic analysis
|
Chlamydia pneumoniae
|
98.0
%
|
|
Journal : J Nat Prod
Title : Identification of Privileged Antichlamydial Natural Products by a Ligand-Based Strategy.
Year : 2017
Volume : 80
Issue : 10
First Page : 2602
Last Page : 2608
Authors : Karhu E, Isojärvi J, Vuorela P, Hanski L, Fallarero A.
Abstract : The obligate intracellular pathogen Chlamydia pneumoniae remains a difficult target for antimicrobial therapy. Owing to the permeability barrier placed by bacterial and host vacuolar membranes, as well as the propensity of the bacterium for persistent infections, treatment failures are common. Despite the urgent need for new antichlamydial compounds, their discovery is challenged by the technically demanding assay procedures and lack of validated targets. An alternative strategy of using naturally occurring compounds and their derivatives against C. pneumoniae is presented. The strategy consists of the application of ligand-based virtual screening to a natural product library of 502 compounds with the ChemGPS-NP chemography tool followed by in vitro antichlamydial assays. The reference set used for the 2D similarity search was constructed of 19 known antichlamydial compounds of plant origin. Based on the similarity screen, 53 virtual hits were selected for in vitro testing. Six compounds (leads) were identified that cause ≥50% C. pneumoniae growth inhibition and showed no impact on host cell viability. The leads fall into completely new antichlamydial chemotypes, one of them being mycophenolic acid (IC50 value 0.3 μM). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.
|
Antichlamydial activity against Chlamydia pneumoniae K7 infected in HL cells after 70 hrs by fluorescent microscopic analysis
|
Chlamydia pneumoniae
|
310.0
nM
|
|
Journal : J Nat Prod
Title : Identification of Privileged Antichlamydial Natural Products by a Ligand-Based Strategy.
Year : 2017
Volume : 80
Issue : 10
First Page : 2602
Last Page : 2608
Authors : Karhu E, Isojärvi J, Vuorela P, Hanski L, Fallarero A.
Abstract : The obligate intracellular pathogen Chlamydia pneumoniae remains a difficult target for antimicrobial therapy. Owing to the permeability barrier placed by bacterial and host vacuolar membranes, as well as the propensity of the bacterium for persistent infections, treatment failures are common. Despite the urgent need for new antichlamydial compounds, their discovery is challenged by the technically demanding assay procedures and lack of validated targets. An alternative strategy of using naturally occurring compounds and their derivatives against C. pneumoniae is presented. The strategy consists of the application of ligand-based virtual screening to a natural product library of 502 compounds with the ChemGPS-NP chemography tool followed by in vitro antichlamydial assays. The reference set used for the 2D similarity search was constructed of 19 known antichlamydial compounds of plant origin. Based on the similarity screen, 53 virtual hits were selected for in vitro testing. Six compounds (leads) were identified that cause ≥50% C. pneumoniae growth inhibition and showed no impact on host cell viability. The leads fall into completely new antichlamydial chemotypes, one of them being mycophenolic acid (IC50 value 0.3 μM). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.
|
Antiviral activity against Chikungunya virus isolate DRDE-06 infected in African green monkey Vero cells by neutral red dye uptake assay
|
Chikungunya virus
|
100.0
nM
|
|
Journal : Bioorg Med Chem
Title : The medicinal chemistry of Chikungunya virus.
Year : 2017
Volume : 25
Issue : 16
First Page : 4219
Last Page : 4244
Authors : da Silva-Júnior EF, Leoncini GO, Rodrigues ÉES, Aquino TM, Araújo-Júnior JX.
Abstract : Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
|
Inhibition of Mycobacterium tuberculosis GuaB2 at 50 uM
|
Mycobacterium tuberculosis
|
83.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors.
Year : 2018
Volume : 28
Issue : 10
First Page : 1714
Last Page : 1718
Authors : Sahu NU, Singh V, Ferraris DM, Rizzi M, Kharkar PS.
Abstract : Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.
|
Inhibition of human IMPDH2 at 10 uM
|
Homo sapiens
|
99.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors.
Year : 2018
Volume : 28
Issue : 10
First Page : 1714
Last Page : 1718
Authors : Sahu NU, Singh V, Ferraris DM, Rizzi M, Kharkar PS.
Abstract : Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.
|
Inhibition of recombinant Cryptococcus neoformans His-tagged IMPDH expressed in Escherichia coli BL21 (DE3) using IMP as substrate in presence of NAD
|
Cryptococcus neoformans
|
120.0
nM
|
|
Journal : Bioorg Med Chem
Title : Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles.
Year : 2018
Volume : 26
Issue : 20
First Page : 5408
Last Page : 5419
Authors : Kummari LK, Butler MS, Furlong E, Blundell R, Nouwens A, Silva AB, Kappler U, Fraser JA, Kobe B, Cooper MA, Robertson AAB.
Abstract : Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.
|
Inhibition of recombinant human His-tagged IMPDH1 expressed in Escherichia coli BL21 (DE3) using IMP as substrate in presence of NAD
|
Homo sapiens
|
260.0
nM
|
|
Journal : Bioorg Med Chem
Title : Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles.
Year : 2018
Volume : 26
Issue : 20
First Page : 5408
Last Page : 5419
Authors : Kummari LK, Butler MS, Furlong E, Blundell R, Nouwens A, Silva AB, Kappler U, Fraser JA, Kobe B, Cooper MA, Robertson AAB.
Abstract : Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.
|
Inhibition of recombinant human His-tagged IMPDH2 expressed in Escherichia coli BL21 (DE3) using IMP as substrate in presence of NAD
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg Med Chem
Title : Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles.
Year : 2018
Volume : 26
Issue : 20
First Page : 5408
Last Page : 5419
Authors : Kummari LK, Butler MS, Furlong E, Blundell R, Nouwens A, Silva AB, Kappler U, Fraser JA, Kobe B, Cooper MA, Robertson AAB.
Abstract : Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.
|
Inhibition of human IMPDH2 using IMP at 10 uM as substrate in presence of NAD+ after 30 mins relative to control
|
Homo sapiens
|
99.9
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents.
Year : 2018
Volume : 158
First Page : 286
Last Page : 301
Authors : Shah CP, Kharkar PS.
Abstract : The enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, and thus regulates the guanine nucleotide pool required for cell proliferation. Of the two isoforms, human IMPDH type 2 (hIMPDH2) is a validated molecular target for potential immunosuppressive, antiviral and anticancer chemotherapy. In search of newer hIMPDH2 inhibitors as potential anticancer agents, three novel series (A: 5-aminoisobenzofuran-1(3H)-one, B: 3,4-dimethoxyaniline and C: benzo[d]-[1,3]dioxol-5-ylmethanamine) were synthesized and evaluated for in vitro and cell-based activities. A total of 37 molecules (29-65) were screened for their in vitro hIMPDH2 inhibition, with particular emphasis on establishing their structure-activity relationship (SAR) trends. Eight compounds (hits, 30, 31, 33-35, 37, 41 and 43) demonstrated significant enzyme inhibition (>70% @ 10 μM); especially the A series molecules were more potent than B series (<70% inhibition @ 10 μM), while C series members were found to be inactive. The hIMPDH2 IC50 values for the hits ranged from 0.36 to 7.38 μM. The hits displaying >80% hIMPDH2 inhibition (30, 33, 35, 41 and 43) were further assessed for their cytotoxic activity against cancer cell lines such as MDA-MB-231 (breast adenocarcinoma), DU145 (prostate carcinoma), U87 MG (glioblastoma astrocytoma) and a normal cell line, NIH-3T3 (mouse embryonic fibroblast) using MTT assay. Most of the compounds exhibited higher cellular potency against cancer cell lines and notably lower toxicity towards NIH-3T3 cells compared to mycophenolic acid (MPA), a prototypical hIMPDH2 inhibitor. Two of the series A hits (30 and 35) were evaluated in human peripheral blood mononuclear cells (hPBMC) assay and found to be better tolerated than MPA. The calculated/predicted molecular and physicochemical properties were satisfactory with reference to drug-likeness. The molecular docking studies clearly demonstrated crucial interactions of the hits with the cofactor-binding site of hIMPDH2, further providing critical information for refining the design strategy. The present study reports the design and discovery of structurally novel hIMPDH2 inhibitors as potential anticancer agents and provides a guide for further research on the development of safe and effective anticancer agents, especially against glioblastoma.
|
Inhibition of human IMPDH2 using IMP as substrate in presence of NAD+ after 30 mins
|
Homo sapiens
|
250.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents.
Year : 2018
Volume : 158
First Page : 286
Last Page : 301
Authors : Shah CP, Kharkar PS.
Abstract : The enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, and thus regulates the guanine nucleotide pool required for cell proliferation. Of the two isoforms, human IMPDH type 2 (hIMPDH2) is a validated molecular target for potential immunosuppressive, antiviral and anticancer chemotherapy. In search of newer hIMPDH2 inhibitors as potential anticancer agents, three novel series (A: 5-aminoisobenzofuran-1(3H)-one, B: 3,4-dimethoxyaniline and C: benzo[d]-[1,3]dioxol-5-ylmethanamine) were synthesized and evaluated for in vitro and cell-based activities. A total of 37 molecules (29-65) were screened for their in vitro hIMPDH2 inhibition, with particular emphasis on establishing their structure-activity relationship (SAR) trends. Eight compounds (hits, 30, 31, 33-35, 37, 41 and 43) demonstrated significant enzyme inhibition (>70% @ 10 μM); especially the A series molecules were more potent than B series (<70% inhibition @ 10 μM), while C series members were found to be inactive. The hIMPDH2 IC50 values for the hits ranged from 0.36 to 7.38 μM. The hits displaying >80% hIMPDH2 inhibition (30, 33, 35, 41 and 43) were further assessed for their cytotoxic activity against cancer cell lines such as MDA-MB-231 (breast adenocarcinoma), DU145 (prostate carcinoma), U87 MG (glioblastoma astrocytoma) and a normal cell line, NIH-3T3 (mouse embryonic fibroblast) using MTT assay. Most of the compounds exhibited higher cellular potency against cancer cell lines and notably lower toxicity towards NIH-3T3 cells compared to mycophenolic acid (MPA), a prototypical hIMPDH2 inhibitor. Two of the series A hits (30 and 35) were evaluated in human peripheral blood mononuclear cells (hPBMC) assay and found to be better tolerated than MPA. The calculated/predicted molecular and physicochemical properties were satisfactory with reference to drug-likeness. The molecular docking studies clearly demonstrated crucial interactions of the hits with the cofactor-binding site of hIMPDH2, further providing critical information for refining the design strategy. The present study reports the design and discovery of structurally novel hIMPDH2 inhibitors as potential anticancer agents and provides a guide for further research on the development of safe and effective anticancer agents, especially against glioblastoma.
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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
|
27.66
%
|
|
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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.99
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-3.8
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.61
%
|
|
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
|
11.44
%
|
|
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
|
18.06
%
|
|
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
|
14.34
%
|
|
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
|
18.06
%
|
|
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
|
14.34
%
|
|
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
|
11.44
%
|
|
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 Zika virus
|
Zika virus
|
0.32
nM
|
|
Journal : J Nat Prod
Title : Diverse Types of Diterpenoids with an Aromatized C Ring from the Twigs of Podocarpus imbricatus.
Year : 2020
Volume : 83
Issue : 8.0
First Page : 2416
Last Page : 2424
Authors : Zhou B,Ren YH,Han YS,Mesplède T,Yue JM
Abstract : An ethanol extract of the powdered twigs of Podocarpus imbricatus afforded 14 new diterpenoids (1-14), which all share an aromatized C ring. These isolates belong to five diterpenoid types that include abietanes (1-3), semperviranes (4-9), totaranes (10-12), a C-17 norabietane (13), and an icetexane (14). Their structures were assigned mainly by analysis of the spectroscopic data, and the absolute configuration of 1 was determined by X-ray crystallography. A biosynthetic pathway for five of the biogenetically related types of diterpenoids was proposed. Compound 7 showed moderate inhibitory activity against Zika virus with an IC value of 2.5 μM.
|
Immunosuppression-mediated cytotoxicity against anti-CD3/anti-CD28-stimulated human PBMC cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Eur J Med Chem
Title : Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid.
Year : 2020
Volume : 189
First Page : 112091
Last Page : 112091
Authors : Siebert A,Cholewiński G,Trzonkowski P,Rachon J
Abstract : Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5'-monophosphate dehydrogenaze (IMPDH) inhibitors.
|
Immunosuppression-mediated antiproliferative activity against human Jurkat T cells assessed as inhibition of cell growth incubated for 48 hrs by VPD450 staining based flow cytometry
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid.
Year : 2020
Volume : 189
First Page : 112091
Last Page : 112091
Authors : Siebert A,Cholewiński G,Trzonkowski P,Rachon J
Abstract : Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5'-monophosphate dehydrogenaze (IMPDH) inhibitors.
|
Immunosuppression-mediated antiproliferative activity against anti-CD3/anti-CD28-stimulated human PBMC cells assessed as inhibition of cell growth incubated for 72 hrs by VPD450 staining based flow cytometry
|
Homo sapiens
|
30.1
nM
|
|
Journal : Eur J Med Chem
Title : Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid.
Year : 2020
Volume : 189
First Page : 112091
Last Page : 112091
Authors : Siebert A,Cholewiński G,Trzonkowski P,Rachon J
Abstract : Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5'-monophosphate dehydrogenaze (IMPDH) inhibitors.
|
Toxicity in mouse MIN6 cells assessed by dehydrogenase activity measured after 48 hrs by CCK-8 assay
|
Mus musculus
|
600.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Catalyzed Activation of Mycophenolic Acid Prodrugs.
Year : 2021
Volume : 12
Issue : 5.0
First Page : 812
Last Page : 816
Authors : Plunk MA,Quintana JM,Darden CM,Lawrence MC,Naziruddin B,Kane RR
Abstract : Mycophenolic acid (MPA) and its morpholino ester prodrug mycophenolate mofetil (MMF) are widely used in solid organ transplantation. These drugs prevent rejection due to their potent inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH), an enzyme vital for lymphocyte proliferation. As a strategy to provide localized immunosuppression in cell transplantation, four mycophenolic acid prodrugs designed to release MPA by two distinct mechanisms were synthesized and characterized. A nitrobenzyl ether prodrug was effectively converted to MPA upon exposure to bacterial nitroreductase, while a propargyl ether was converted to the active drug by immobilized Pd nanoparticles. In vitro, both prodrugs were inactive against IMPDH and exhibited reduced toxicity relative to the active drug, suggesting their potential for providing localized immunosuppression.
|
Antiviral activity against HCoV-NL63 infected in Rhesus macaque LLC-MK2 cells incubated for 72 hrs by RT-PCR method
|
Human coronavirus NL63
|
180.0
nM
|
|
Journal : J Med Chem
Title : Chinese Therapeutic Strategy for Fighting COVID-19 and Potential Small-Molecule Inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13205
Last Page : 13227
Authors : Choudhry N,Zhao X,Xu D,Zanin M,Chen W,Yang Z,Chen J
Abstract : The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 20 million people infected worldwide with an average mortality rate of 3.6%. This virus poses major challenges to public health, as it not only is highly contagious but also can be transmitted by asymptomatic infected individuals. COVID-19 is clinically difficult to manage due to a lack of specific antiviral drugs or vaccines. In this article, Chinese therapy strategies for treating COVID-19 patients, including current applications of traditional Chinese medicine (TCM), are comprehensively reviewed. Furthermore, 72 small molecules from natural products and TCM with reported antiviral activity against human coronaviruses (CoVs) are identified from published literature, and their potential applications in combating SARS-CoV-2 are discussed. Among these, the clinical efficacies of some accessible drugs such as remdesivir (RDV) and favipiravir (FPV) for COVID-19 are emphatically summarized. We hope this review provides a foundation for managing the worsening pandemic and developing antivirals against SARS-CoV-2.
|
Cytotoxicity against human SH-SY5Y cells assessed as growth inhibition measured by SRB assay
|
Homo sapiens
|
560.0
nM
|
|
