title: Interactions of long-chain homologues of colchicine with tubulin.
abstract: Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straight-chain acyl moieties, have been synthesized. These compounds show high cytotoxic activity at the nanomolar level against the tumoral cell lines HT-29, MCF-7 and A549. Some of them exhibit activities in the picomolar range against the HT-29 line and are thus two to three orders of magnitude more cytotoxic than colchicine. In this specific cell line, the activities were found to be closely related to the length of the acyl carbon chain, an increase in the latter giving rise to an increase in the cytotoxicity with a maximum in the range of 10-12 carbon atoms, followed by a decrease in activity with still longer chains. Some of the compounds inhibit microtubule assembly and induce the formation of abnormal polymers and present in most cases better apparent affinity constants than colchicine. In addition, at IC50concentrations the analogues block the cell cycle of A549 cells in the G2/M phase. Molecular docking studies suggest that, while interactions of the colchicine analogues with the colchicine binding site at β-tubulin are still present, the increase in the acyl chain length leads to the progressive development of new interactions, not present in colchicine itself, with the neighboring α-tubulin subunit. Indeed, sufficiently long acyl chains span the intradimer interface and contact with a hydrophobic groove in α-tubulin. It is worth noting that some of the compounds show cytotoxicity at concentrations three orders of magnitude lower than colchicine. Their pharmacological use in cancer therapy could possibly be performed with lower dosages and be thus endowed with less acute toxicity problems than in the case of colchicine.
authors.affiliation: Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Marzo-Mas
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, 13385, Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Barbier
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, 13385, Marseille, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Breuzard
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, 13385, Marseille, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Allegro
authors.affiliation: Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Falomir
authors.affiliation: Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Spain. Electronic address: jmurga@uji.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Murga
authors.affiliation: Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carda
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, 13385, Marseille, France. Electronic address: vincent.peyrot@univ-amu.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.affiliation: Depart. de Q. Orgánica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain.
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Marco
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D003078:Colchicine
keywords: Abnormal polymerization; Colchicine; Cytotoxicity; Docking studies; Microtubules; Tubulin