2. Academic Validation
  3. Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin

Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin

  • J Med Chem. 2015 Apr 9;58(7):3209-22. doi: 10.1021/acs.jmedchem.5b00155.
Romeo Romagnoli 1,  Pier Giovanni Baraldi 1,  Maria Kimatrai Salvador 1,  Filippo Prencipe 1,  Carlota Lopez-Cara 2,  Santiago Schiaffino Ortega 2,  Andrea Brancale 3,  Ernest Hamel 4,  Ignazio Castagliuolo 5,  Stefania Mitola 6,  Roberto Ronca 6,  Roberta Bortolozzi 7,  Elena Porcù 7,  Giuseppe Basso 7,  Giampietro Viola 7
Affiliations

Affiliations

  • 1 †Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
  • 2 ‡Departamento de Quimica Organica y Farmaceutica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071, Granada, Spain.
  • 3 §School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, U.K.
  • 4 ∥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.
  • 5 #Dipartimento di Medicina Molecolare, Università di Padova, 35121 Padova, Italy.
  • 6 ⊥Dipartimento di Medicina Molecolare e Traslazionale, Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25121 Brescia, Italy.
  • 7 ∞Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
PMID: 25785605 DOI: 10.1021/acs.jmedchem.5b00155
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.

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