title: Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents.
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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: pgb@unife.it.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Carlota
authors.initials: C
authors.lastname: Lopez-Cara
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Maria Kimatrai
authors.initials: MK
authors.lastname: Salvador
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.affiliation: Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Lead Discovery Center Gmbh, Dortmund, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nussbaumer
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Marcella
authors.initials: M
authors.lastname: Bassetto
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: 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.
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Fu
authors.affiliation: 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.
authors.lastname: Yang-Gao
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Su-Zhan
authors.initials: SZ
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address: giampietro.viola1@unipd.it.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013876:Thiophenes; D014404:Tubulin
keywords: Anticancer agents; Apoptosis; Colchicine site; Thiophene; Tubulin