title: Synthesis and antitumor activity of 1,5-disubstituted 1,2,4-triazoles as cis-restricted combretastatin analogues.
abstract: A series of 1-aryl-5-(3',4',5'-trimethoxyphenyl) derivatives and their related 1-(3',4',5'-trimethoxyphenyl)-5-aryl-1,2,4-triazoles, designed as cis-restricted combretastatin analogues, were synthesized and evaluated for antiproliferative activity, inhibitory effects on tubulin polymerization, cell cycle effects, and apoptosis induction. Their activity was greater than, or comparable with, that of the reference compound CA-4. Flow cytometry studies showed that HeLa and Jurkat cells treated with the most active compounds 4l and 4o were arrested in the G2/M phase of the cell cycle in a concentration dependent manner. This effect was accompanied by apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and PARP cleavage. Compound 4l was also shown to have potential antivascular activity, since it induced endothelial cell shape change in vitro and disrupted the sprouting of endothelial cells in the chick aortic ring assay.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 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: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Carlota
authors.initials: C
authors.lastname: Lopez Cara
authors.forename: Maria Dora
authors.initials: MD
authors.lastname: Carrion
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Longchuan
authors.initials: L
authors.lastname: Chen
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: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape; D002478:Cells, Cultured; D002642:Chick Embryo; D003078:Colchicine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C550171:1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-1,2,4-triazole; C550172:5-(3-Chloro-4-ethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001632:Bibenzyls; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014230:Triazoles; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D003078:Colchicine