title: Regioselective Suzuki coupling of dihaloheteroaromatic compounds as a rapid strategy to synthesize potent rigid combretastatin analogues.
abstract: Combretastatin A-4 (CA-4) is a potent tubulin depolymerizing agent able to inhibit tumor growth and with antivascular effects. Although it is in clinical trials, the search for novel analogues that may display better/different features is still ongoing. In this manuscript we describe the synthesis of novel constrained analogues of CA-4 obtained in only two synthetic steps exploiting a regioselective Suzuki coupling of dihalogenated heteroaromatic and alicyclic compounds. All the compounds synthesized have been evaluated for cytotoxicity and for their ability to inhibit tubulin assembly. One of them, 38, displayed low nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to that of CA-4 and a better pharmacokinetic profile, but most important of all, this synthetic strategy may pave the way for the easy and rapid generation of novel rigid analogues of combretastatins.
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale A. Avogadro, Via Bovio 6, 28100 Novara, Italy.
authors.forename: Sewan
authors.initials: S
authors.lastname: Theeramunkong
authors.forename: Antonio
authors.initials: A
authors.lastname: Caldarelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Massarotti
authors.forename: Silvio
authors.initials: S
authors.lastname: Aprile
authors.forename: Diego
authors.initials: D
authors.lastname: Caprioglio
authors.forename: Roberta
authors.initials: R
authors.lastname: Zaninetti
authors.forename: Alessia
authors.initials: A
authors.lastname: Teruggi
authors.forename: Tracey
authors.initials: T
authors.lastname: Pirali
authors.forename: Giorgio
authors.initials: G
authors.lastname: Grosa
authors.forename: Gian Cesare
authors.initials: GC
authors.lastname: Tron
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin; D003078:Colchicine