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Biochem Biophys Res Commun. 2015 Oct 23;466(3):418-25. doi: 10.1016/j.bbrc.2015.09.041. Epub 2015 Sep 11.

Binding of dihydroxynaphthyl aryl ketones to tubulin colchicine site inhibits microtubule assembly.

Author information

1
Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile.
2
Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile; Instituto de EtnoFarmacologia (IDE), Universidad Arturo Prat, Iquique, Chile.
3
Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile; Instituto de EtnoFarmacologia (IDE), Universidad Arturo Prat, Iquique, Chile; Facultad de Química, Pontificia Universidad Católica de Chile, Santiago, Chile.
4
Instituto de EtnoFarmacologia (IDE), Universidad Arturo Prat, Iquique, Chile; Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
5
Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
6
Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
7
Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. Electronic address: monaster@uchile.cl.

Abstract

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.

KEYWORDS:

Bioinformatics; Colchicine; Dihydroxynaphthyl aryl ketones; Microtubules; Photo acylation; Thermophoresis

PMID:
26365353
DOI:
10.1016/j.bbrc.2015.09.041
[Indexed for MEDLINE]

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