Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase.
J Med Chem
; 35(4): 663-76, 1992 Feb 21.
Article
em En
| MEDLINE
| ID: mdl-1542093
ABSTRACT
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.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Timidilato Sintase
/
Desenho de Fármacos
/
Indóis
/
Antineoplásicos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
1992
Tipo de documento:
Article