Design,synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents |
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| Institution: | 1. Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy;2. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, B-3000 Leuven, Belgium;3. Lead Discovery Center Gmbh, Dortmund, Germany;4. School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK;5. Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310009, People’s Republic of China;6. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA;7. Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy;1. Inst. of Pharmaceutical Sciences, Eidgenössische Technische Hochschule (ETH) Zürich, Wolfgang-Pauli Strasse 10, Zürich, CH-8093, Switzerland;1. Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, A.P., India;2. Dr. Reddy''s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India;3. Manipal College of Pharmaceutical Science, Manipal University, Manipal 576104, India;4. School of Pharmacy, University of Queensland, Brisbane QLD4072, Australia;5. Zephase Therapeutics (an incubated company at DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, Egypt;3. Department of Pharmacology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Str. 11, D-44227 Dortmund, Germany;2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Str. 6, D-44227 Dortmund, Germany;3. IMD Natural Solutions GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany;1. Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Campus I, Castelo Branco, João Pessoa, Paraíba CEP 58059-900, Brazil;2. Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, PE 50670-910, Brazil;3. Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, João Pessoa, Paraíba 58059-900, Brazil;4. Programa de Pós-Graduação em Inovação Terapêutica, Universidade Federal de Pernambuco, Campus I, Recife, PE 50670-901, Brazil;5. Federal University of Paraíba, Campus I, João Pessoa, PB 58051-970, Brazil;6. Instituto de Quimica e Biotecnologia, Universidade Federal de Alagoas, Maceió, AL 57072-970, Brazil;7. Departamento de Ciências Biológicas, Universidade Estadual da Paraíba, CCBSA, João Pessoa, PB 58070-540, Brazil |
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| Abstract: | 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. |
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| Keywords: | Tubulin Thiophene Anticancer agents Colchicine site Apoptosis |
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