Binding of dihydroxynaphthyl aryl ketones to tubulin colchicine site inhibits microtubule assembly.
Biochem Biophys Res Commun
; 466(3): 418-25, 2015 Oct 23.
Article
em En
| MEDLINE
| ID: mdl-26365353
Dihydroxynaphthyl aryl ketones 1-5 have been evaluated for their abilities to inhibit microtubule assembly and the binding to tubulin. Compounds 3, 4 and 5 displayed competitive inhibition against colchicine binding, and docking analysis showed that they bind to the tubulin colchicine-binding pocket inducing sheets instead of microtubules. Remarkable differences in biological activity observed among the assayed compounds seem to be related to the structure and position of the aryl substituent bonded to the carbonyl group. Compounds 2, 3 and 4, which contain a heterocyclic ring, presented higher affinity for tubulin compared to the carbocyclic analogue 5. Compound 4 showed the best affinity of the series, with an IC50 value of 2.1 µM for microtubule polymerization inhibition and a tubulin dissociation constant of 1.0 ± 0.2 µM, as determined by thermophoresis. Compound 4 was more efficacious in disrupting microtubule assembly in vitro than compound 5 although it contains the trimethoxyphenyl ring present in colchicine. Hydrogen bonds with Asn101 of α-tubulin seem to be responsible for the higher affinity of compound 4 respects to the others.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
/
Colchicina
/
Cetonas
/
Microtúbulos
Limite:
Animals
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Chile
País de publicação:
Estados Unidos