SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL 2,6-DIAMINOBENZ[CD]INDOLE INHIBITORS OF THYMIDYLATE SYNTHASE USING THE PROTEIN-STRUCTURE AS A GUIDE

The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N-6-[4-(morpholinosulfonyl)benzyl]-N-6-methyl-2,6-diaminobenz[cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.