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

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. 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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (22), p.9296-9309
Main Authors: Romagnoli, Romeo, Baraldi, Pier Giovanni, Lopez-Cara, Carlota, Preti, Delia, Aghazadeh Tabrizi, Mojgan, Balzarini, Jan, Bassetto, Marcella, Brancale, Andrea, Fu, Xian-Hua, Gao, Yang, Li, Jun, Zhang, Su-Zhan, Hamel, Ernest, Bortolozzi, Roberta, Basso, Giuseppe, Viola, Giampietro
Format: Article
Language:English
Subjects:
Animals
Antimitotic Agents - chemical synthesis
Antimitotic Agents - chemistry
Antimitotic Agents - pharmacology
Antimitotic Agents - toxicity
Apoptosis - drug effects
Caspases - metabolism
Cell Cycle - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry Techniques, Synthetic
Colchicine - metabolism
Enzyme Activation - drug effects
Female
Gene Expression Regulation, Neoplastic - drug effects
Humans
Mice
Mice, Inbred BALB C
Mitochondria - drug effects
Models, Molecular
Protein Multimerization - drug effects
Protein Structure, Quaternary
Proto-Oncogene Proteins c-bcl-2 - metabolism
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - pharmacology
Thiophenes - toxicity
Tubulin - chemistry
X-Linked Inhibitor of Apoptosis Protein - metabolism
Xenograft Model Antitumor Assays
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Summary:The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. 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 position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure–activity 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–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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4013938