title: Discovery and optimization of a series of 2-aryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazoles as novel anticancer agents.
abstract: A new series of tubulin polymerization inhibitors based on the 2-aryl/heteroaryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole scaffold was synthesized and evaluated for growth inhibition activity on a panel of cancer cell lines, cell cycle effects, and in vivo potency. Structure-activity relationships were elucidated with various substitutions at the 2-position of the thiazole skeleton. Hydrophobic moieties, such as phenyl and 3-thienyl, were well tolerated at this position, and variation of the phenyl substituents had remarkable effects on potency. The most active compound (3b) induced apoptosis through the mitochondrial pathway with activation of caspase-3. We also showed that it has potential antivascular activity since it reduced in vitro endothelial cell migration and disrupted capillary-like tube formation at noncytotoxic concentrations. Furthermore, compound 3b significantly reduced the growth of the HT-29 xenograft in a nude mouse model, suggesting that 3b is a promising new antimitotic agent with clinical potential.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, 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: 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: Elena
authors.initials: E
authors.lastname: Porcù
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 / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D062385:Hydroxybenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C575284:(4-amino-2-(thiophen-3-yl)thiazol-5-yl)(3,4,5-trimethoxyphenyl)methanone; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D062385:Hydroxybenzoates; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013844:Thiazoles; D013876:Thiophenes; D050257:Tubulin Modulators; D053148:Caspase 3