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Bioorg Med Chem Lett. 2013 Aug 15;23(16):4669-73. doi: 10.1016/j.bmcl.2013.06.009. Epub 2013 Jun 12.

Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity.

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  • 1Universidade Federal de Mato Grosso do Sul, Instituto de Química, Laboratório LP4, Av. Filinto Müller, 1555, 79070-900 Campo Grande (MS), Brazil.

Abstract

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

Combretastatin A-4; Cytotoxicity; Diaryl selenide; Diaryl sulfide; Tubulin

PMID:
23810282
[PubMed - indexed for MEDLINE]
PMCID:
PMC3774136
Free PMC Article
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