Synthesis and Evaluation of Diaryl Sulfides and Diaryl Selenide Compounds for Antitubulin and Cytotoxic Activity

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2013 Jul 2

PMID 23810282

Citations 16

Authors

Edson Dos A Dos Santos

Ernest Hamel

Ruoli Bai

James C Burnett

Camila Santos Suniga Tozatti

Danielle Bogo

Renata T Perdomo

Alexandra M M Antunes

M Matilde Marques

Maria de F C Matos

Denis P DE Lima

Affiliations

Soon will be listed here.

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.

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