title: Solution-phase parallel synthesis and biological evaluation of combretatriazoles.
abstract: Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins containing a triazole ring (combretatriazoles). To achieve this, we have developed a column chromatography-free parallel solution-phase synthesis that exploits the reaction between azides and alpha-keto phosphorus ylids, which is known to regioselectively generate the 1,5-disubstituted triazoles. The prepared compounds were screened as antitubulinic agents, allowing us to identify three new compounds with high potency, two of which show a new mechanism of action that induces cells to appear multinucleated and display a high number of mitotic spindles.
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Bovio 6, 28100 Novara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cafici
authors.forename: Tracey
authors.initials: T
authors.lastname: Pirali
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Condorelli
authors.forename: Erika
authors.initials: E
authors.lastname: Del Grosso
authors.forename: Alberto
authors.initials: A
authors.lastname: Massarotti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorba
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Gian Cesare
authors.initials: GC
authors.lastname: Tron
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008855:Microscopy, Electron, Scanning; D012428:Ruthenium / Q000737:chemistry; D012996:Solutions / Q000737:chemistry; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D012996:Solutions; D013267:Stilbenes; D014230:Triazoles; D050257:Tubulin Modulators; D012428:Ruthenium; C058728:fosbretabulin