Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase

• Published in: Journal of medicinal chemistry 1992-02, Vol.35 (4), p.663-676
• Main Authors: Varney, Michael D, Marzoni, Gifford P, Palmer, Cindy L, Deal, Judith G, Webber, Stephanie, Welsh, Katherine M, Bacquet, Russell J, Bartlett, Charlotte A, Morse, Catharine A
• Format: Article
• Language: English
• Subjects: Alkylation; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Cell Division - drug effects; Chemistry; Crystallization; Drug Design; Escherichia coli - enzymology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Leukemia L1210 - pathology; Molecular Structure; Organic chemistry; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Preparations and properties; Structure-Activity Relationship; Thymidylate Synthase - antagonists & inhibitors; Tumor Cells, Cultured; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00082a006

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benz[cd]indole-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 Ki'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-aminobenz[cd]indol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion. The 2,6-diaminobenz[cd]indoles 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.