Design, synthesis and biological evaluation of 2-alkoxycarbonyl-3-anilinoindoles as a new class of potent inhibitors of tubulin polymerization

Author:

Romagnoli, Romeo

Prencipe, Filippo

Oliva, Paola

Kimatrai Salvador, Maria

Brancale, Andrea

Ferla, Salvatore

Hamel,Ernest

Viola, Giampietro

Bortolozzi, Roberta

Persoons, Leentje

Balzarini, Jan

Liekens, Sandra

Schols, Dominique
Author Address

Dipartimento di Scienze Chimiche e Farmaceutiche, Universit 224; di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it., School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK., 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., Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Universit 224; di Padova, 35131 Padova, Italy; Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti 4, 35128 Padova, Italy., Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Universit 224; di Padova, 35131 Padova, Italy., Rega Institute for Medical Research, KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium.,

Abstract:

A new class of inhibitors of tubulin polymerization based on the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)indole molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. The results presented show that the methoxy substitution and location on the indole nucleus plays an important role in inhibition of cell growth, and the most favorable position for the substituent was at C-6. In addition, a small-size ester function (methoxy/ethoxycarbonyl) at the 2-position of the indole core was desirable. Also, analogues that were alkylated with methyl, ethyl or n-propyl groups or had a benzyl moiety on the N-1 indolic nitrogen retained activity equivalent to those observed in the parent N-1H analogues. The most promising compounds of the series were 2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-5-methoxyindole 3f and 1-methyl-2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-6-methoxy-indole 3w, both of which target tubulin at the colchicine site with antitubulin activities comparable to that of the reference compound combretastatin A-4. Copyright © 2020 Elsevier Inc. All rights reserved.

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