title: Binding of dihydroxynaphthyl aryl ketones to tubulin colchicine site inhibits microtubule assembly.
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.
authors.affiliation: Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile.
authors.forename: Eunices
authors.initials: E
authors.lastname: Gutierrez
authors.affiliation: Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile; Instituto de EtnoFarmacologia (IDE), Universidad Arturo Prat, Iquique, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Benites
authors.affiliation: 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.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Valderrama
authors.affiliation: 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.
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
authors.affiliation: Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Julien
authors.initials: J
authors.lastname: Verrax
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Esteban
authors.initials: E
authors.lastname: Nova
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Villanelo
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Maturana
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Escobar
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Lagos
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. Electronic address: monaster@uchile.cl.
authors.forename: Octavio
authors.initials: O
authors.lastname: Monasterio
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002645:Chickens; D003078:Colchicine / Q000378:metabolism* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007659:Ketones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007659:Ketones; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine
keywords: Bioinformatics; Colchicine; Dihydroxynaphthyl aryl ketones; Microtubules; Photo acylation; Thermophoresis