title: New ligands of the tubulin colchicine site based on X-ray structures.
abstract: Colchicine site ligands have proved to be potent inhibitors of tubulin polymerization, which leads them not only to display cytotoxic effects but also vascular disrupting effects on tumour neovasculature. In recent years, many compounds have been designed, synthesized and evaluated in order to improve the potency, stability and physicochemical properties of these agents with the aim of developing an agent that could reach the clinical assay level. Here we analyze the eleven X-ray structures of tubulin in complex with ligands at the colchicine site by dividing it into four different zones of interaction, we review the new compounds that have appeared in the literature since 2008 and that were designed based on any of these X-ray structures and, finally, we describe our latest results in the design of new potent antimitotic indole derivatives that have confirmed the flexibility of one of the zones described for the colchicine site.
authors.forename: Raquel
authors.initials: R
authors.lastname: Álvarez
authors.forename: Manuel
authors.initials: M
authors.lastname: Medarde
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Campus "Miguel de Unamuno", Salamanca, E-37007, Spain. pelaez@usal.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Peláez
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003078:Colchicine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine