Crystal-Structure-Based Design and Synthesis of Benzindole-Containing Inhibitors of Thymidylate Synthase

Article abstract of DOI:10.1021/jm00082a006

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benzindole-containing inhibitors of thymidylate synthase (TS) are described.The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region.Combination of favored substituents for each region led to inhibitors with K_i's against the human enzyme in the range of 10-20 nM.Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells.The inhibitors were synthesized from substituted 6-aminobenzindol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion.The 2,6-diaminobenzindoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.