title: Synthesis and evaluation of 1,5-disubstituted tetrazoles as rigid analogues of combretastatin A-4 with potent antiproliferative and antitumor activity.
abstract: Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 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: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Fu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Su-Zhan
authors.initials: SZ
authors.lastname: Zhang
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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C570919:1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-tetrazole; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D013267:Stilbenes; D013777:Tetrazoles; D050257:Tubulin Modulators; D020169:Caspases; C058728:fosbretabulin