title: Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin.
abstract: A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3',4',5'-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3-27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate.
authors.affiliation: †Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: †Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: †Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Maria Kimatrai
authors.initials: MK
authors.lastname: Salvador
authors.affiliation: †Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Prencipe
authors.affiliation: ‡Departamento de Quimica Organica y Farmaceutica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071, Granada, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: Lopez-Cara
authors.affiliation: ‡Departamento de Quimica Organica y Farmaceutica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071, Granada, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Schiaffino Ortega
authors.affiliation: §School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, U.K.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
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, Maryland 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: #Dipartimento di Medicina Molecolare, Università di Padova, 35121 Padova, Italy.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.affiliation: ⊥Dipartimento di Medicina Molecolare e Traslazionale, Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25121 Brescia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.affiliation: ⊥Dipartimento di Medicina Molecolare e Traslazionale, Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25121 Brescia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronca
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: Elena
authors.initials: E
authors.lastname: Porcù
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.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002642:Chick Embryo; D003078:Colchicine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001572:Benzofurans; D014404:Tubulin; D003078:Colchicine