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.

doi:10.1021/jm8006933

Paper

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.

Published Sep 25, 2008 · A. Gangjee, Yibin Qiu, Wei Li

Journal of medicinal chemistry

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50

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Abstract

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(3 H)-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 (IC 50 = 40 nM) and human DHFR (IC 50 = 20 nM) known to date. The nonclassical analogues 5- 13 were moderately potent against human TS with IC 50 values ranging from 0.11 to 4.6 microM. 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-substituted 2-amino-4-oxo-6-methylthieno[2,3-d]pyrimidine scaffold is highly conducive to dual human TS-DHFR inhibitory activity.

In Vitro Study

Study Snapshot

The 5-substituted 2-amino-4-oxo-6-methylthieno[2,3-d]pyrimidine scaffold is highly conducive to dual human thymidylate synthase-dihydrofolate reductase inhibitory activity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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.

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References

Citations

Synthesis of 2-Amino-quinazolin-4(3H)-ones Using 2-Bromo-N-phenylbenzamide and Cyanamide Ullmann Cross-Coupling.

This study developed a cost-effective, accessible method for synthesizing 2-amino-3-substituted quinoline-4(3H)-ones and N-phenylbenzamide derivatives using 2-bromo-N-phenylbenzamide and cyanamide under air conditions.

Synthesis and in vitro antitumor evaluation of new thieno[2,3-d]pyrimidine derivatives as EGFR and DHFR inhibitors.

New thienopyrimidine derivatives show high antitumor activity against various cancer cell lines, with compounds 6e and 10e showing high inhibitory activity against EGFR-TK and compounds 7d and 10e showing high inhibitory activity against DHFR.

An updated review of chemical compounds with anti-Toxoplasma gondii activity.

A safe chemotherapy for toxoplasmosis should focus on metabolic differences between the parasite and mammalian host, targeting relevant molecular targets.

New thieno[2,3-b]pyridine-fused pyrimidin-4(3H)-ones as potential thymidylate synthase inhibitors: Synthesis, SAR, in vitro and in silico study

New thieno[2,3-b]pyridine-fused pyrimidinones show promising thymidylate synthase inhibitory activity, with pyrimidinones 2b and 2c showing promising cytotoxicity against cancer cells and being drug-like.

Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors

Compound 20 is a strong antitumor agent and potent inhibitor of dihydrofolate reductase, with potential for use in cancer therapy.