Synthesis and evaluation of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.

摘要: In an effort to optimize the structural requirements for combined cytostatic and cytotoxic effects in single agents, a series of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines 3-7 were synthesized evaluated as inhibitors receptor tyrosine kinases (RTKs) well thymidylate synthase (TS). The synthesis these compounds involved nucleophilic displacement common intermediate 5-bromo/5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate aryl thiols. A novel four step synthetic scheme was developed which is more efficient relative previously reported six-step sequence. Biological evaluation indicated dual activity RTKs human TS (hTS). VEGFR-2 assay, compound 5 equipotent standard semaxanib better than inhibitor pemetrexed, hTS assay. Compounds 3, 6 7 nanomolar several fold pemetrexed.