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

Abstract

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.

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

“…Since furans and pyrroles are both five-membered aromatic ring systems, with a heteroatom contributing one lone pair of electrons to its aromaticity, it was envisioned that the oxidative coupling reaction could also be adopted for substitution at the 6- position of 20 to afford target molecules 6 – 16 . We17, 18, 37, 38 have extensively utilized the oxidative thiolation procedure in their synthesis of both 5- and 6-arylthio substituted pyrrolo[2,3- d ]pyrimidine containing antifolates.…”

Three‐component reaction for synthesis of2‐amino‐6‐aryl‐5‐(phenylamino)‐3,7‐dihydro‐4H‐pyrrolo[2,3‐d]pyrimidin‐4‐one derivatives in water

“…Typically, Jyostna group 8 reported the synthesis of new pyrrolo[2,3‐ d ]pyrimidines with heteroaryl substitution at fifth position through sulfur linker as heteroaryl groups, and evaluated their activities against human colon cancer cell lines. Gangjee group 9 studied the synthesis of 10 benzylthiopyrrolo[2,3‐ d ]‐pyrimidines with potential inhibitors of thymidylate synthase using 2,6‐diaminopyrimidin‐4(3 H )‐one and 1‐chloropropan‐2‐one as starting materials. In addition, Klepper, Wilding, and Kilic‐Kurt groups 10 also reported structurally diverse pyrrolo[2,3‐ d ]‐pyrimidine derivatives using 2,6‐diaminopyrimidin‐4(3 H )‐one as substrate, respectively.…”