2. Academic Validation
  3. Design, synthesis, in vitro and in vivo biological evaluation of 2-amino-3-aroylbenzo[b]furan derivatives as highly potent tubulin polymerization inhibitors

Design, synthesis, in vitro and in vivo biological evaluation of 2-amino-3-aroylbenzo[b]furan derivatives as highly potent tubulin polymerization inhibitors

  • Eur J Med Chem. 2020 Aug 15;200:112448. doi: 10.1016/j.ejmech.2020.112448.
Paola Oliva 1,  Romeo Romagnoli 2,  Stefano Manfredini 3,  Andrea Brancale 4,  Salvatore Ferla 4,  Ernest Hamel 5,  Roberto Ronca 6,  Federica Maccarinelli 6,  Arianna Giacomini 6,  Fatlum Rruga 7,  Elena Mariotto 7,  Giampietro Viola 8,  Roberta Bortolozzi 9
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy.
  • 2 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy. Electronic address: [email protected].
  • 3 Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
  • 4 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
  • 5 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.
  • 6 Dipartimento di Medicina Molecolare e Traslazionale Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25123, Brescia, Italy.
  • 7 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy.
  • 8 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy; Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti 4, 35128, Padova, Italy. Electronic address: [email protected].
  • 9 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy. Electronic address: [email protected].
PMID: 32417696 DOI: 10.1016/j.ejmech.2020.112448
Abstract

A new class of inhibitors of tubulin polymerization based on the 2-amino-3-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular scaffold was synthesized and evaluated for in vivo and in vitro biological activity. These derivatives were synthesized with different electron-releasing or electron-withdrawing substituents at one of the C-4 through C-7 positions. Methoxy substitution and location on the benzene part of the benzo[b]furan ring played an important role in affecting antiproliferative activity, with the greatest activity occurring with the methoxy group at the C-6 position, the least with the substituent at C-4. The same effect was also observed with ethoxy, methyl or bromine at the C-6 position of the benzo[b]furan skeleton, with the 6-ethoxy-2-amino-3-(3',4',5'-trimethoxybenzoyl)benzo[b]furan derivative 4f as the most promising compound of the series. This compound showed remarkable antiproliferative activity (IC50: 5 pM) against the Daoy medulloblastoma cell line, and 4f was nearly devoid of toxicity on healthy human lymphocytes and astrocytes. The potent antiproliferative activity of 4f was derived from its inhibition of tubulin polymerization by binding to the colchicine site. The compound was also examined for in vivo activity, showing higher potency at 15 mg/kg compared with the reference compound combretastatin A-4 phosphate at 30 mg/kg against a syngeneic murine mammary tumor.

Keywords

Benzo[b]furan; Colchicine binding site; Inhibition tubulin assembly; In vivo activity; Microtubules.

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