Concise Synthesis and Biological Evaluation of 2-Aroyl-5-Amino Benzo[b]thiophene Derivatives As a Novel Class of Potent Antimitotic Agents

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• 作者：Romeo Romagnoli ; Pier Giovanni Baraldi ; Carlota Lopez-Cara ; Delia Preti ; Mojgan Aghazadeh Tabrizi ; Jan Balzarini ; Marcella Bassetto ; Andrea Brancale ; Xian-Hua Fu ; Yang Gao ; Jun Li ; Su-Zhan Zhang ; Ernest Hamel ; Roberta Bortolozzi ; Giuseppe Basso ; Giampietro Viola
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9296-9309
• 全文大小：568K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3鈥?4鈥?5鈥?trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure鈥揳ctivity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c鈥?b>e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC₅₀ values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice.