Structure-based design of new KSP-Eg5 inhibitors assisted by a targeted multicomponent reaction.
Chembiochem
; 15(10): 1471-80, 2014 Jul 07.
Article
em En
| MEDLINE
| ID: mdl-24943831
ABSTRACT
An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50 =1.49 µM, EC50 =3.63 µM) and 22 (IC50 =1.37 µM, EC50 =6.90 µM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.
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Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
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Desenho de Fármacos
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Cinesinas
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Antineoplásicos
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article