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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 16; pp. 4669 - 4673
• Main Authors: dos Santos, Edson dos A., Hamel, Ernest, Bai, Ruoli, Burnett, James C., Tozatti, Camila Santos Suniga, Bogo, Danielle, Perdomo, Renata T., Antunes, Alexandra M.M., Marques, M. Matilde, Matos, Maria de F.C., de Lima, Dênis P.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2013; Elsevier
• Subjects: antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - toxicity; Bibenzyls - chemical synthesis; Bibenzyls - chemistry; Bibenzyls - pharmacology; Binding Sites; breast neoplasms; Breast Neoplasms - drug therapy; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; colchicine; Combretastatin A-4; Cytotoxicity; Diaryl selenide; Diaryl sulfide; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Models, Molecular; Pharmacology & Pharmacy; Physical Sciences; polymerization; Science & Technology; selenium; Selenium - chemistry; Selenium - pharmacology; sulfides; Sulfides - chemistry; Sulfides - pharmacology; sulfur; Tubulin; Tubulin Modulators - chemical synthesis; Tubulin Modulators - pharmacology; Tumor Cells, Cultured; Diaryl sulfide; Combretastatin A-4; Cytotoxicity; Diaryl selenide; Tubulin; ANALOGS; TUBULIN POLYMERIZATION; ANTINEOPLASTIC AGENTS; SULFUR; COLCHICINE; BIOLOGICAL EVALUATION; INHIBITORS; DERIVATIVES
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.009

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.