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 |
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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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Matilde ; Matos, Maria de F.C. ; de Lima, Dênis P.</creator><creatorcontrib>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.</creatorcontrib><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.</description><identifier>ISSN: 0960-894X</identifier><identifier>ISSN: 1464-3405</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.06.009</identifier><identifier>PMID: 23810282</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>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</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-08, Vol.23 (16), p.4669-4673</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><rights>2013 Elsevier Ltd. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c545t-2a2ad7d39c76b49966a9d599f0d88d273e50dca1ea00defc3a45f1e7247c2d9d3</citedby><cites>FETCH-LOGICAL-c545t-2a2ad7d39c76b49966a9d599f0d88d273e50dca1ea00defc3a45f1e7247c2d9d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2013.06.009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23810282$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>dos Santos, Edson dos A.</creatorcontrib><creatorcontrib>Hamel, Ernest</creatorcontrib><creatorcontrib>Bai, Ruoli</creatorcontrib><creatorcontrib>Burnett, James C.</creatorcontrib><creatorcontrib>Tozatti, Camila Santos Suniga</creatorcontrib><creatorcontrib>Bogo, Danielle</creatorcontrib><creatorcontrib>Perdomo, Renata T.</creatorcontrib><creatorcontrib>Antunes, Alexandra M.M.</creatorcontrib><creatorcontrib>Marques, M. 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 & 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. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.</description><subject>antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Bibenzyls - chemical synthesis</subject><subject>Bibenzyls - chemistry</subject><subject>Bibenzyls - pharmacology</subject><subject>Binding Sites</subject><subject>breast neoplasms</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Cell Proliferation - drug effects</subject><subject>colchicine</subject><subject>Combretastatin A-4</subject><subject>Cytotoxicity</subject><subject>Diaryl selenide</subject><subject>Diaryl sulfide</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Female</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Models, Molecular</subject><subject>polymerization</subject><subject>selenium</subject><subject>Selenium - chemistry</subject><subject>Selenium - pharmacology</subject><subject>sulfides</subject><subject>Sulfides - chemistry</subject><subject>Sulfides - pharmacology</subject><subject>sulfur</subject><subject>Tubulin</subject><subject>Tubulin Modulators - chemical synthesis</subject><subject>Tubulin Modulators - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0960-894X</issn><issn>1464-3405</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9rFDEYh4Modl39Ah50jl5mzN-ZCYggRVuh4KEWvIVs8k6bJZusSWZxv71Zpy16MZfAm-f95U0ehF4T3BFM-vfbbrMzvqOYsA73HcbyCVoR3vOWcSyeohWWPW5HyX-coRc5bzEmHHP-HJ1RNhJMR7pC--tjKHeQXW50sA0ctJ91cTE0cWqs0-nomzz7yVlYiIcaeAi12Ji428c52NxMMVWiuDJvZu_CH9ocSyzxlzONNsUdXDm-RM8m7TO8ut_X6ObL5-_nl-3Vt4uv55-uWiO4KC3VVNvBMmmGfsOl7HstrZBywnYcLR0YCGyNJqAxtjAZprmYCAyUD4ZaadkafVxy9_NmB9ZAKEl7tU9uVx-gonbq35Pg7tRtPCg2DJywvga8uw9I8ecMuaidywa81wHinBXhhAoxCo4rShfUpJhzgunxGoLVSZXaqpMqdVKlcK-qqtr05u8BH1se3FTg7QJMOip9m1xWN9c1QVSPjLK61ujDQkD9yIODpLJxEAxYl8AUZaP73wS_AfFxsq4</recordid><startdate>20130815</startdate><enddate>20130815</enddate><creator>dos Santos, Edson dos A.</creator><creator>Hamel, Ernest</creator><creator>Bai, Ruoli</creator><creator>Burnett, James C.</creator><creator>Tozatti, Camila Santos Suniga</creator><creator>Bogo, Danielle</creator><creator>Perdomo, Renata T.</creator><creator>Antunes, Alexandra M.M.</creator><creator>Marques, M. Matilde</creator><creator>Matos, Maria de F.C.</creator><creator>de Lima, Dênis P.</creator><general>Elsevier Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130815</creationdate><title>Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c545t-2a2ad7d39c76b49966a9d599f0d88d273e50dca1ea00defc3a45f1e7247c2d9d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - toxicity</topic><topic>Bibenzyls - chemical synthesis</topic><topic>Bibenzyls - chemistry</topic><topic>Bibenzyls - pharmacology</topic><topic>Binding Sites</topic><topic>breast neoplasms</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Cell Proliferation - drug effects</topic><topic>colchicine</topic><topic>Combretastatin A-4</topic><topic>Cytotoxicity</topic><topic>Diaryl selenide</topic><topic>Diaryl sulfide</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Female</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Models, Molecular</topic><topic>polymerization</topic><topic>selenium</topic><topic>Selenium - chemistry</topic><topic>Selenium - pharmacology</topic><topic>sulfides</topic><topic>Sulfides - chemistry</topic><topic>Sulfides - pharmacology</topic><topic>sulfur</topic><topic>Tubulin</topic><topic>Tubulin Modulators - chemical synthesis</topic><topic>Tubulin Modulators - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>dos Santos, Edson dos A.</creatorcontrib><creatorcontrib>Hamel, Ernest</creatorcontrib><creatorcontrib>Bai, Ruoli</creatorcontrib><creatorcontrib>Burnett, James C.</creatorcontrib><creatorcontrib>Tozatti, Camila Santos Suniga</creatorcontrib><creatorcontrib>Bogo, Danielle</creatorcontrib><creatorcontrib>Perdomo, Renata T.</creatorcontrib><creatorcontrib>Antunes, Alexandra M.M.</creatorcontrib><creatorcontrib>Marques, M. Matilde</creatorcontrib><creatorcontrib>Matos, Maria de F.C.</creatorcontrib><creatorcontrib>de Lima, Dênis P.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>dos Santos, Edson dos A.</au><au>Hamel, Ernest</au><au>Bai, Ruoli</au><au>Burnett, James C.</au><au>Tozatti, Camila Santos Suniga</au><au>Bogo, Danielle</au><au>Perdomo, Renata T.</au><au>Antunes, Alexandra M.M.</au><au>Marques, M. 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 & 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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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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