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Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents

Romagnoli, Romeo, Baraldi, Pier Giovanni, Lopez-Cara, Carlota, Salvador, Maria Kimatrai, Preti, Delia, Tabrizi, Mojgan Aghazadeh, Balzarini, Jan, Nussbaumer, Peter, Bassetto, Marcella, Brancale, Andrea ORCID:, Fu, Xian-Hua, Yang-Gao, Li, Jun, Zhang, Su-Zhan, Hamel, Ernest, Bortolozzi, Roberta, Basso, Giuseppe and Viola, Giampietro 2014. Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents. Bioorganic & Medicinal Chemistry 22 (18) , pp. 5097-5109. 10.1016/j.bmc.2013.12.030

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In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2′,5′-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC50 = 17–130 nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Tubulin; Thiophene; Anticancer agents; Colchicine site; Apoptosis
Publisher: Elsevier
ISSN: 0968-0896
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 23 December 2013
Last Modified: 05 Jan 2024 17:40

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