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Synthesis of 2-amino-4-oxo-5-substitutedbenzylthiopyrrolo[2,3-d]-pyrimidines as potential inhibitors of thymidylate synthase

✍ Scribed by Aleem Gangjee; Hiteshkumar D. Jain; Jaclyn Phan; Roy L. Kisliuk

Publisher
Journal of Heterocyclic Chemistry
Year
2005
Tongue
English
Weight
59 KB
Volume
42
Category
Article
ISSN
0022-152X

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✦ Synopsis

A series of ten novel 2-amino-4-oxo-5-[(substitutedbenzyl)thio]pyrrolo [2,3-d]pyrimidines 2-11 were synthesized as potential inhibitors of thymidylate synthase and as antitumor agents. The analogues contain various electron withdrawing and electron donating substituents on the benzylsulfanyl ring of the side chains and were synthesized from the key intermediate 2-amino-4-oxo-6-methylpyrrolo[2,3-d]pyrimidine, 14. Appropriately substituted benzyl mercaptans were appended to the 5-position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against human, Escherichia coli and Toxoplasma gondii thymidylate synthase and against human, Escherichia coli and Toxoplasma gondii dihydrofolate reductase. The most potent inhibitor, (6) which has a 4'-methoxy substituent on the side chain, has an IC 50 =25 µM against human thymidylate synthase. Contrary to analogues of general structure 1, electron donating or electron withdrawing substituents on the side chain of 2-11 had little or no influence on the human thymidylate synthase inhibitory activity.

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