Varney M D, Palmer C L, Deal J G, Webber S, Welsh K M, Bartlett C A, Morse C A, Smith W W, Janson C A
Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
J Med Chem. 1995 May 26;38(11):1892-903. doi: 10.1021/jm00011a009.
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 N6-[4-(morpholinosulfonyl)benzyl]-N6-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.
