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

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...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2013-08, Vol.23 (16), p.4669-4673
Hauptverfasser: 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.
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container_end_page 4673
container_issue 16
container_start_page 4669
container_title Bioorganic & medicinal chemistry letters
container_volume 23
creator 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.
description 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.
doi_str_mv 10.1016/j.bmcl.2013.06.009
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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. 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Matilde</creatorcontrib><creatorcontrib>Matos, Maria de F.C.</creatorcontrib><creatorcontrib>de Lima, Dênis P.</creatorcontrib><title>Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity</title><title>Bioorganic &amp; medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>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. 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Matilde</au><au>Matos, Maria de F.C.</au><au>de Lima, Dênis P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity</atitle><jtitle>Bioorganic &amp; medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-08-15</date><risdate>2013</risdate><volume>23</volume><issue>16</issue><spage>4669</spage><epage>4673</epage><pages>4669-4673</pages><issn>0960-894X</issn><issn>1464-3405</issn><eissn>1464-3405</eissn><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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23810282</pmid><doi>10.1016/j.bmcl.2013.06.009</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elsevier ScienceDirect Journals
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
colchicine
Combretastatin A-4
Cytotoxicity
Diaryl selenide
Diaryl sulfide
Drug Screening Assays, Antitumor
Female
Humans
Inhibitory Concentration 50
Models, Molecular
polymerization
selenium
Selenium - chemistry
Selenium - pharmacology
sulfides
Sulfides - chemistry
Sulfides - pharmacology
sulfur
Tubulin
Tubulin Modulators - chemical synthesis
Tubulin Modulators - pharmacology
Tumor Cells, Cultured
title Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity
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