Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase
| Autor: | C. A. Morse, Deal Judith G, Marzoni Gifford P, Russell J. Bacquet, Varney Michael D, Katherine M. Welsh, Cynthia Louise Palmer, Carol L. J. Booth, Charlotte A. Bartlett, Stephanie Webber |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Indoles
Alkylation Stereochemistry Antineoplastic Agents Thymidylate synthase Piperazines Structure-Activity Relationship chemistry.chemical_compound X-Ray Diffraction Drug Discovery Escherichia coli Tumor Cells Cultured Animals Humans Structure–activity relationship Leukemia L1210 Indole test chemistry.chemical_classification Binding Sites Molecular Structure biology Thymidylate Synthase Enzyme chemistry Enzyme inhibitor Drug Design biology.protein Lactam Molecular Medicine Crystallization Lead compound Cell Division |
| Zdroj: | Journal of Medicinal Chemistry. 35:663-676 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|