New arylthioindoles, potent inhibitors of tubulin polymerization. 2. Structure activity relationships and molecular modeling studies

Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, De Martino, Gabriella, Edler, Michael C., La Regina, Guiseppe, Coluccio, Antonio, Barbera, Maria Chiara, Barrow, Denise, Nicholson, Robert I., Chiosis, Gabriela, Hamel, Ernst, Artico, Marino and Silvestri, Romano 2006. New arylthioindoles, potent inhibitors of tubulin polymerization. 2. Structure activity relationships and molecular modeling studies. Journal of Medicinal Chemistry 49 (3) , pp. 947-954. 10.1021/jm050809s

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Abstract

Arylthioindoles (ATIs) that possess a 3-methoxyphenylthio or a 3,5-dimethoxyphenylthio moiety at position 2 of the indole ring were effective tubulin assembly inhibitors, but weak inhibitors of MCF-7 cell growth. ATIs bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety were potent tubulin polymerization inhibitors, with IC50s in the 2.0 (35) to 4.5 (37) ?M range. They also inhibited MCF-7 cell growth at nanomolar concentrations. The 3,4,5-trimethoxy substituted ATIs showed potencies comparable to those of the reference compounds colchicine and combretastatin A-4 in both tubulin assembly and cell growth inhibition assays. Dynamics simulation studies correlate well with the observed experimental data. Furthermore, from careful analysis of the biological and in silico data, we can now hypothesize a basic pharmacophore for this class of compounds.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
ISSN:	00222623
Last Modified:	05 Jan 2024 06:00
URI:	https://orca.cardiff.ac.uk/id/eprint/896

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