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 hu man thymidylate synthase (TS) are described. The compounds are charact erized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor fonyl)benzyl] -N-6-methyl-2,6-diaminobenz[cd]indole glucuronate (i). Active compound s from this series showed human TS inhibition constants below the 10 n M level and were potent, selective submicromolar antitumor agents in c ell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a sub stituted 1-cyano-8-nitronaphthalene.