title: Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara , 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Carlota
authors.initials: C
authors.lastname: Lopez-Cara
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Marcella
authors.initials: M
authors.lastname: Bassetto
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Fu
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
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: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003078:Colchicine / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014404:Tubulin / Q000737:chemistry; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D050256:Antimitotic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013876:Thiophenes; D014404:Tubulin; D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases; D003078:Colchicine