The biological importance of microtubules make them an interesting target for the development of anticancer drugs. The 2-(3’,4’,5’-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 methoxy substitution pattern on the benzene portion of the benzo[b]thiophene moiety played an important role in affecting antiproliferative activity. The structure-activity relationship established that the best activities were obtained with the amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-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. These findings indicate that this compound is a promising new antimitotic agent with high therapeutic potential as a clinically useful anticancer agent.

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

ROMAGNOLI, Romeo;BARALDI, Pier Giovanni;PRETI, Delia;AGHAZADEH TABRIZI, Mojgan;
2013

Abstract

The biological importance of microtubules make them an interesting target for the development of anticancer drugs. The 2-(3’,4’,5’-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 methoxy substitution pattern on the benzene portion of the benzo[b]thiophene moiety played an important role in affecting antiproliferative activity. The structure-activity relationship established that the best activities were obtained with the amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-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. These findings indicate that this compound is a promising new antimitotic agent with high therapeutic potential as a clinically useful anticancer agent.
Romagnoli, Romeo; Baraldi, Pier Giovanni; C., Lopez Cara; Preti, Delia; AGHAZADEH TABRIZI, Mojgan; J., Balzarini; M., Bassetto; A., Brancale; X. H., Fu; Y., Gao; J., Li; S. Z., Zhang; E., Hamel; R., Bortolozzi; G., Basso; G., Viola
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1888318
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