title: Synthesis and biological evaluation of 2-substituted-4-(3',4',5'-trimethoxyphenyl)-5-aryl thiazoles as anticancer agents.
abstract: Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me >> N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. rmr@unife.it
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Maria Kimatrai
authors.initials: MK
authors.lastname: Salvador
authors.forename: M Encarnacion
authors.initials: ME
authors.lastname: Camacho
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Marcella
authors.initials: M
authors.lastname: Bassetto
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013844:Thiazoles; D014404:Tubulin; D003078:Colchicine