The Experts below are selected from a list of 1791 Experts worldwide ranked by ideXlab platform
Aleem Gangjee - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis biological evaluation and x ray crystal structure of novel classical 6 5 6 tricyclic benzo 4 5 thieno 2 3 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xin Zhang, Roy L Kisliuk, Vivian Cody, Xilin Zhou, Jennifer Piraino, Aleem GangjeeAbstract:Abstract Classical antifolates (4–7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH3 substituents inhibited human (h) TS (IC50 = 0.26–0.8 μM), but not hDHFR. Substitution of the 2-CH3 with a 2-NH2 increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC50 = 0.09–0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.
-
conformationally restricted analogues of trimethoprim 2 6 diamino 8 substituted purines as potential Dihydrofolate Reductase Inhibitors from pneumocystis carinii and toxoplasma gondii
ChemInform, 2010Co-Authors: Aleem Gangjee, Anil Vasudevan, Sherry F QueenerAbstract:Twenty-two 2,6-diamino-8-substituted purines (2-23) were synthesized, in which rotation around the two flexible bonds of trimethoprim (TMP), linking the pyrimidine ring to the side chain phenyl ring, was restricted by incorporation into a purine ring, in an attempt to increase the potency and selectivity of TMP against Dihydrofolate Reductase (DHFR) from the organisms that often cause fatal opportunistic infections in patients with AIDS, i.e., Pneumocystis carinii (pc) and Toxoplasma gondii (tg). The syntheses of analogues 2-20 were achieved via a one-pot reaction of 2,4,5,6-tetraaminopyrimidine and the appropriately substituted benzaldehyde or phenyl acetaldehyde, in acidic methoxyethanol. Analogues 21-23 were synthesized via nucleophilic displacement of 2,6-diamino-8-(chloromethyl)purine with the appropriate anilines or 2-naphthalenethiol. The compounds were evaluated as Inhibitors of pcDHFR and tgDHFR with rat liver (rl) DHFR as the mammalian reference enzyme. Compound 11, the 3',4'-dichlorophenyl analogue, was as potent as TMP and had a selectivity ratio of 13 for pcDHFR, which ranked it as one of the three most selective Inhibitors of pcDHFR (compared to rlDHFR) known to date. It also displayed a selectivity ratio of 38 for tgDHFR. None of the other analogues showed any improvement compared to TMP in potency or selectivity. In the preclinical in vitro screening program of the National Cancer Institute, compound 11 showed a GI50 of 10(-6) M for the inhibition of the growth of 17 tumor cell lines.
-
2 4 diamino 5 methyl 6 substituted arylthio furo 2 3 d pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Aleem Gangjee, Hiteshkumar D Jain, Jaclyn Phan, Xin Guo, Sherry F Queener, Roy L KisliukAbstract:Abstract A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}- l -glutamic acid 5 and 11 nonclassical antifolates 6–16 were designed, synthesized, and evaluated as Inhibitors of Dihydrofolate Reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds 6–16 were synthesized from 20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid 21 followed by saponification gave the classical analog 5. Compound 5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog 5 was a nanomolar inhibitor and remarkably selective inhibitor of Pneumocystis carinii DHFR and Mycobacterium avium DHFR at 263-fold and 2107-fold, respectively, compared to mammalian DHFR. The nonclassical analogs 6–16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.
-
design synthesis and x ray crystal structures of 2 4 diaminofuro 2 3 d pyrimidines as multireceptor tyrosine kinase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Aleem Gangjee, Yibin Zeng, Michael A Ihnat, Linda A Warnke, Dixy W Green, Lu Lin, Vivian Cody, Jim Pace, Sherry F QueenerAbstract:To optimize dual receptor tyrosine kinase (RTK) and Dihydrofolate Reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4A, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5A) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2-13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8-C9 unsaturated compounds 2-7 and catalytic reduction gave the saturated 8-13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-beta were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.
-
design synthesis and x ray crystal structure of classical and nonclassical 2 amino 4 oxo 5 substituted 6 ethylthieno 2 3 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors and as potential antitumor agents
Journal of Medicinal Chemistry, 2009Co-Authors: Aleem Gangjee, Roy L Kisliuk, Vivian Cody, Jim Pace, Jennifer Piraino, J MakinAbstract:N-{4-[(2-Amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)thio]benzoyl}-l-glutamic acid 2 and 13 nonclassical analogues 2a−2m were synthesized as potential dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors and as antitumor agents. The key intermediate in the synthesis was 2-amino-6-ethyl-5-iodothieno[2,3-d]pyrimidin-4(3H)-one, 7, to which various arylthiols were attached at the 5-position. Coupling 8 with l-glutamic acid diethyl ester and saponification afforded 2. X-ray crystal structures of 2 and 1 (the 6-methyl analogue of 2), DHFR, and NADPH showed for the first time that the thieno[2,3-d]pyrimidine ring binds in a “folate” mode. Compound 2 was an excellent dual inhibitor of human TS (IC50 = 54 nM) and human DHFR (IC50 = 19 nM) and afforded nanomolar GI50 values against tumor cells in culture. The 6-ethyl substitution in 2 increases both the potency (by 2−3 orders of magnitude) as well as the spectrum of tumor inhibition in vitro compared to the 6-methyl analogue 1...
Sherry F Queener - One of the best experts on this subject based on the ideXlab platform.
-
conformationally restricted analogues of trimethoprim 2 6 diamino 8 substituted purines as potential Dihydrofolate Reductase Inhibitors from pneumocystis carinii and toxoplasma gondii
ChemInform, 2010Co-Authors: Aleem Gangjee, Anil Vasudevan, Sherry F QueenerAbstract:Twenty-two 2,6-diamino-8-substituted purines (2-23) were synthesized, in which rotation around the two flexible bonds of trimethoprim (TMP), linking the pyrimidine ring to the side chain phenyl ring, was restricted by incorporation into a purine ring, in an attempt to increase the potency and selectivity of TMP against Dihydrofolate Reductase (DHFR) from the organisms that often cause fatal opportunistic infections in patients with AIDS, i.e., Pneumocystis carinii (pc) and Toxoplasma gondii (tg). The syntheses of analogues 2-20 were achieved via a one-pot reaction of 2,4,5,6-tetraaminopyrimidine and the appropriately substituted benzaldehyde or phenyl acetaldehyde, in acidic methoxyethanol. Analogues 21-23 were synthesized via nucleophilic displacement of 2,6-diamino-8-(chloromethyl)purine with the appropriate anilines or 2-naphthalenethiol. The compounds were evaluated as Inhibitors of pcDHFR and tgDHFR with rat liver (rl) DHFR as the mammalian reference enzyme. Compound 11, the 3',4'-dichlorophenyl analogue, was as potent as TMP and had a selectivity ratio of 13 for pcDHFR, which ranked it as one of the three most selective Inhibitors of pcDHFR (compared to rlDHFR) known to date. It also displayed a selectivity ratio of 38 for tgDHFR. None of the other analogues showed any improvement compared to TMP in potency or selectivity. In the preclinical in vitro screening program of the National Cancer Institute, compound 11 showed a GI50 of 10(-6) M for the inhibition of the growth of 17 tumor cell lines.
-
novel 2 hydrazino pyrimidin 4 3h one derivatives as potential Dihydrofolate Reductase Inhibitors
Journal of Heterocyclic Chemistry, 2010Co-Authors: Mariam S Degani, Seema Bag, Ranjeet Bairwa, Nilesh R Tawari, Sherry F QueenerAbstract:Novel substituted 2-hydrazino-pyrimidin-4(3H)-one derivatives were synthesized and examined for their antifolate activity against DHFR from Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). A novel, simple, and feasible methodology was developed for the synthesis of the titled compounds. Amongst these, compound 6-phenyl-2-(2-(1-(thiophen-2-yl) ethylidene)hydrazinyl) pyrimidin-4(3H)-one exhibited 17.74 μM activity against pcDHFR. J. Heterocyclic Chem., (2010).
-
2 4 diamino 5 methyl 6 substituted arylthio furo 2 3 d pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Aleem Gangjee, Hiteshkumar D Jain, Jaclyn Phan, Xin Guo, Sherry F Queener, Roy L KisliukAbstract:Abstract A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}- l -glutamic acid 5 and 11 nonclassical antifolates 6–16 were designed, synthesized, and evaluated as Inhibitors of Dihydrofolate Reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds 6–16 were synthesized from 20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid 21 followed by saponification gave the classical analog 5. Compound 5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog 5 was a nanomolar inhibitor and remarkably selective inhibitor of Pneumocystis carinii DHFR and Mycobacterium avium DHFR at 263-fold and 2107-fold, respectively, compared to mammalian DHFR. The nonclassical analogs 6–16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.
-
design synthesis and x ray crystal structures of 2 4 diaminofuro 2 3 d pyrimidines as multireceptor tyrosine kinase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Aleem Gangjee, Yibin Zeng, Michael A Ihnat, Linda A Warnke, Dixy W Green, Lu Lin, Vivian Cody, Jim Pace, Sherry F QueenerAbstract:To optimize dual receptor tyrosine kinase (RTK) and Dihydrofolate Reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4A, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5A) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2-13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8-C9 unsaturated compounds 2-7 and catalytic reduction gave the saturated 8-13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-beta were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.
-
synthesis of three carbon atom bridged 2 4 diaminopyrrolo 2 3 d pyrimidines as nonclassical Dihydrofolate Reductase Inhibitors
ChemInform, 2006Co-Authors: Aleem Gangjee, Sherry F QueenerAbstract:A series of seven nonclassical three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrirnidines 1a-g were synthesized as potential Inhibitors of Dihydrofolate Reductase. Selective oxidation of diols 7a-g affords α-hydroxy ketones 8a-g. Subsequent condensation with malononitrile gave the requisite 2-amino-3-cyano-4-substituted furan precursors 9a-g. Cyclocondensation with guanidine in refluxing ethanol in one step affords the three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrimidines 1a-g. Preliminary biological results indicated that these compounds showed moderate inhibitory activities against Dihydrofolate Reductases from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium and rat liver with IC50 values in the 0.66 μM - 70.1 μM range and some compounds had marginal selectivity for T. gondii Dihydrofolate Reductase.
Roy L Kisliuk - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis biological evaluation and x ray crystal structure of novel classical 6 5 6 tricyclic benzo 4 5 thieno 2 3 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xin Zhang, Roy L Kisliuk, Vivian Cody, Xilin Zhou, Jennifer Piraino, Aleem GangjeeAbstract:Abstract Classical antifolates (4–7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH3 substituents inhibited human (h) TS (IC50 = 0.26–0.8 μM), but not hDHFR. Substitution of the 2-CH3 with a 2-NH2 increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC50 = 0.09–0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.
-
2 4 diamino 5 methyl 6 substituted arylthio furo 2 3 d pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Aleem Gangjee, Hiteshkumar D Jain, Jaclyn Phan, Xin Guo, Sherry F Queener, Roy L KisliukAbstract:Abstract A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}- l -glutamic acid 5 and 11 nonclassical antifolates 6–16 were designed, synthesized, and evaluated as Inhibitors of Dihydrofolate Reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds 6–16 were synthesized from 20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid 21 followed by saponification gave the classical analog 5. Compound 5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog 5 was a nanomolar inhibitor and remarkably selective inhibitor of Pneumocystis carinii DHFR and Mycobacterium avium DHFR at 263-fold and 2107-fold, respectively, compared to mammalian DHFR. The nonclassical analogs 6–16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.
-
design synthesis and x ray crystal structure of classical and nonclassical 2 amino 4 oxo 5 substituted 6 ethylthieno 2 3 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors and as potential antitumor agents
Journal of Medicinal Chemistry, 2009Co-Authors: Aleem Gangjee, Roy L Kisliuk, Vivian Cody, Jim Pace, Jennifer Piraino, J MakinAbstract:N-{4-[(2-Amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)thio]benzoyl}-l-glutamic acid 2 and 13 nonclassical analogues 2a−2m were synthesized as potential dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors and as antitumor agents. The key intermediate in the synthesis was 2-amino-6-ethyl-5-iodothieno[2,3-d]pyrimidin-4(3H)-one, 7, to which various arylthiols were attached at the 5-position. Coupling 8 with l-glutamic acid diethyl ester and saponification afforded 2. X-ray crystal structures of 2 and 1 (the 6-methyl analogue of 2), DHFR, and NADPH showed for the first time that the thieno[2,3-d]pyrimidine ring binds in a “folate” mode. Compound 2 was an excellent dual inhibitor of human TS (IC50 = 54 nM) and human DHFR (IC50 = 19 nM) and afforded nanomolar GI50 values against tumor cells in culture. The 6-ethyl substitution in 2 increases both the potency (by 2−3 orders of magnitude) as well as the spectrum of tumor inhibition in vitro compared to the 6-methyl analogue 1...
-
potent dual thymidylate synthase and Dihydrofolate Reductase Inhibitors classical and nonclassical 2 amino 4 oxo 5 arylthio substituted 6 methylthieno 2 3 d pyrimidine antifolates
Journal of Medicinal Chemistry, 2008Co-Authors: Aleem Gangjee, Yibin Qiu, Roy L KisliukAbstract:N-{4-[(2-Amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl}-l-glutamic acid (4) and nine nonclassical analogues 5−13 were synthesized as potential dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors. The key intermediate in the synthesis was 2-amino-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (16), which was converted to the 5-bromo-substituted compound 17 followed by an Ullmann reaction to afford 5−13. The classical analogue 4 was synthesized by coupling the benzoic acid derivative 19 with diethyl l-glutamate and saponification. Compound 4 is the most potent dual inhibitor of human TS (IC50 = 40 nM) and human DHFR (IC50 = 20 nM) known to date. The nonclassical analogues 5−13 were moderately potent against human TS with IC50 values ranging from 0.11 to 4.6 μM. The 4-nitrophenyl analogue 7 was the most potent compound in the nonclassical series, demonstrating potent dual inhibitory activities against human TS and DHFR. This study indicated that the 5-substit...
-
design synthesis and biological evaluation of classical and nonclassical 2 amino 4 oxo 5 substituted 6 methylpyrrolo 3 2 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Journal of Medicinal Chemistry, 2008Co-Authors: Aleem Gangjee, Jie Yang, Roy L KisliukAbstract:We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl}-l-glutamic acid 4 and 11 nonclassical analogues 5–15 as potential dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,2-dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl l-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal Inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.
Jeffrey Skolnick - One of the best experts on this subject based on the ideXlab platform.
-
chemical space of escherichia coli Dihydrofolate Reductase Inhibitors new approaches for discovering novel drugs for old bugs
Medicinal Research Reviews, 2019Co-Authors: Bharath Srinivasan, Sam Tonddastnavaei, Ambrish Roy, Hongyi Zhou, Jeffrey SkolnickAbstract:Escherichia coli Dihydrofolate Reductase is an important enzyme that is essential for the survival of the Gram-negative microorganism. Inhibitors designed against this enzyme have demonstrated application as antibiotics. However, either because of poor bioavailability of the small-molecules resulting from their inability to cross the double membrane in Gram-negative bacteria or because the microorganism develops resistance to the antibiotics by mutating the DHFR target, discovery of new antibiotics against the enzyme is mandatory to overcome drug-resistance. This review summarizes the field of DHFR inhibition with special focus on recent efforts to effectively interface computational and experimental efforts to discover novel classes of Inhibitors that target allosteric and active-sites in drug-resistant variants of EcDHFR.
-
rational design of novel allosteric Dihydrofolate Reductase Inhibitors showing antibacterial effects on drug resistant escherichia coli escape variants
ACS Chemical Biology, 2017Co-Authors: Bharath Srinivasan, Sam Tonddastnavaei, Joao V Rodrigues, Eugene I Shakhnovich, Jeffrey SkolnickAbstract:In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein’s surface to overcome the above problems. Dihydrofolate Reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate Dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule Inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds...
-
Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants
2017Co-Authors: Bharath Srinivasan, Joao V Rodrigues, Sam Tonddast-navaei, Eugene Shakhnovich, Jeffrey SkolnickAbstract:In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein’s surface to overcome the above problems. Dihydrofolate Reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate Dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule Inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These Inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known Inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR Inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of Inhibitors targeting a unique pocket on EcDHFR
Vivian Cody - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis biological evaluation and x ray crystal structure of novel classical 6 5 6 tricyclic benzo 4 5 thieno 2 3 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xin Zhang, Roy L Kisliuk, Vivian Cody, Xilin Zhou, Jennifer Piraino, Aleem GangjeeAbstract:Abstract Classical antifolates (4–7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH3 substituents inhibited human (h) TS (IC50 = 0.26–0.8 μM), but not hDHFR. Substitution of the 2-CH3 with a 2-NH2 increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC50 = 0.09–0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.
-
design synthesis and x ray crystal structures of 2 4 diaminofuro 2 3 d pyrimidines as multireceptor tyrosine kinase and Dihydrofolate Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Aleem Gangjee, Yibin Zeng, Michael A Ihnat, Linda A Warnke, Dixy W Green, Lu Lin, Vivian Cody, Jim Pace, Sherry F QueenerAbstract:To optimize dual receptor tyrosine kinase (RTK) and Dihydrofolate Reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4A, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5A) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2-13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8-C9 unsaturated compounds 2-7 and catalytic reduction gave the saturated 8-13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-beta were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.
-
design synthesis and x ray crystal structure of classical and nonclassical 2 amino 4 oxo 5 substituted 6 ethylthieno 2 3 d pyrimidines as dual thymidylate synthase and Dihydrofolate Reductase Inhibitors and as potential antitumor agents
Journal of Medicinal Chemistry, 2009Co-Authors: Aleem Gangjee, Roy L Kisliuk, Vivian Cody, Jim Pace, Jennifer Piraino, J MakinAbstract:N-{4-[(2-Amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)thio]benzoyl}-l-glutamic acid 2 and 13 nonclassical analogues 2a−2m were synthesized as potential dual thymidylate synthase (TS) and Dihydrofolate Reductase (DHFR) Inhibitors and as antitumor agents. The key intermediate in the synthesis was 2-amino-6-ethyl-5-iodothieno[2,3-d]pyrimidin-4(3H)-one, 7, to which various arylthiols were attached at the 5-position. Coupling 8 with l-glutamic acid diethyl ester and saponification afforded 2. X-ray crystal structures of 2 and 1 (the 6-methyl analogue of 2), DHFR, and NADPH showed for the first time that the thieno[2,3-d]pyrimidine ring binds in a “folate” mode. Compound 2 was an excellent dual inhibitor of human TS (IC50 = 54 nM) and human DHFR (IC50 = 19 nM) and afforded nanomolar GI50 values against tumor cells in culture. The 6-ethyl substitution in 2 increases both the potency (by 2−3 orders of magnitude) as well as the spectrum of tumor inhibition in vitro compared to the 6-methyl analogue 1...
-
selective pneumocystis carinii Dihydrofolate Reductase Inhibitors design synthesis and biological evaluation of new 2 4 diamino 5 substituted furo 2 3 d pyrimidines
ChemInform, 1998Co-Authors: Aleem Gangjee, Xin Guo, Sherry F Queener, Vivian Cody, Nikolai Galitsky, Joseph R Luft, Walter PangbornAbstract:Nonclassical antifolates, 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines 3−12 with bridge region variations of C8−S9, C8−N9, and C8−O9 and 1-naphthyl, 2-naphthyl, 2-phenoxyphenyl, 4-phenoxyphenyl, and 2-biphenyl side chains were synthesized as phenyl ring appended analogues of previously reported 2,4-diamino-5-(anilinomethyl)furo[2,3-d]pyrimidines. The phenyl ring appended analogues were designed to specifically interact with Phe69 of Dihydrofolate Reductase (DHFR) from Pneumocystis carinii (pc) to afford selective Inhibitors of pcDHFR. Additional substituted phenyl side chains which include 2,5-dichloro, 3,4-dichloro, 3,4,5-trichloro, 3-methoxy, and 2,5-dimethoxy analogues 13−17 were also synthesized. The compounds were prepared by nucleophilic displacement of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine(2) with the appropriate thiol, amine, or naphthol. Compound 2 was obtained from 2,4-diamino-6-hydroxypyrimidine and 1,3-dichloroacetone. The compounds were evaluated as Inhibitors against DHFR fro...