Discovery and Optimization of a Series of 2-Aryl-4-Amino-5-(3′,4′,5′-trimethoxybenzoyl)Thiazoles as Novel Anticancer Agents

被引：59

作者：

Romagnoli, Romeo ^{[1
]}

Baraldi, Pier Giovanni ^{[1
]}

Salvador, Maria Kimatrai ^{[1
]}

Preti, Delia ^{[1
]}

Tabrizi, Mojgan Aghazadeh ^{[1
]}

Brancale, Andrea ^{[2
]}

Fu, Xian-Hua ^{[3
]}

Li, Jun ^{[3
]}

Zhang, Su-Zhan ^{[3
]}

Hamel, Ernest ^{[4
]}

Bortolozzi, Roberta ^{[5
]}

Porcu, Elena ^{[5
]}

Basso, Giuseppe ^{[5
]}

Viola, Giampietro ^{[5
]}

机构：

[1] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy

[2] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales

[3] Zhejiang Univ, China Natl Minist Educ, Affiliated Hosp 2, Key Lab Canc Prevent & Intervent,Sch Med,Canc Ins, Hangzhou 310009, Zhejiang, Peoples R China

[4] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[5] Univ Padua, Lab Oncoematol, Dipartimento Salute Donna & Bambino, I-35131 Padua, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 11期

关键词：

MICROTUBULE DYNAMICS; NATURAL-PRODUCTS; TUBULIN; COLCHICINE; BINDING; GROWTH; COMBRETASTATIN-A4; GENERATION; APOPTOSIS; DOMAIN;

D O I：

10.1021/jm300388h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5433 / 5445

页数：13

共 43 条

[1] Microtubule structure and its stabilisation [J].