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

• Published in: Bioorganic chemistry 2020-04, Vol.97, p.103665-103665, Article 103665
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Design; Drug Screening Assays, Antitumor; Humans; Indole; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Microtubules; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Structure-activity relationship; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103665

[Display omitted] •Small molecules based on the indole nucleus are inhibitors of tubulin assembly.•Most of these compounds exhibited broad-spectrum antiproliferative activity.•The most potent compounds induced G2/M arrest and apoptosis.•A good correlation was observed between antiproliferative and antitubulin activities.•Compounds 3f and 3w are potent antiproliferative and antitubulin agents. 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.