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

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 and Schols, Dominique 2020. Design, synthesis and biological evaluation of 2-alkoxycarbonyl-3-anilinoindoles as a new class of potent inhibitors of tubulin polymerization. Bioorganic Chemistry 97 , 103665. 10.1016/j.bioorg.2020.103665
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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier
ISSN: 0045-2068
Date of First Compliant Deposit: 26 May 2020
Date of Acceptance: 11 February 2020
Last Modified: 17 Mar 2021 02:45
URI: http://orca.cf.ac.uk/id/eprint/131916

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