Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins
Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl g...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-08, Vol.55 (15), p.6724-6737 |
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| creator | Abad, Andrés López-Pérez, José L del Olmo, Esther García-Fernández, Luis F Francesch, Andrés Trigili, Chiara Barasoain, Isabel Andreu, José M Díaz, J. Fernando San Feliciano, Arturo |
| description | Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series. |
| doi_str_mv | 10.1021/jm2017573 |
| format | Article |
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Fernando ; San Feliciano, Arturo</creator><creatorcontrib>Abad, Andrés ; López-Pérez, José L ; del Olmo, Esther ; García-Fernández, Luis F ; Francesch, Andrés ; Trigili, Chiara ; Barasoain, Isabel ; Andreu, José M ; Díaz, J. Fernando ; San Feliciano, Arturo</creatorcontrib><description>Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm2017573</identifier><identifier>PMID: 22607205</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antimitotic Agents - chemical synthesis ; Antimitotic Agents - pharmacology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Binding, Competitive ; Cell Cycle - drug effects ; Cell Line, Tumor ; Cell Proliferation ; Drug Screening Assays, Antitumor ; Humans ; Microtubules - drug effects ; Microtubules - ultrastructure ; Models, Molecular ; Podophyllotoxin - analogs & derivatives ; Podophyllotoxin - chemical synthesis ; Podophyllotoxin - pharmacology ; Stereoisomerism ; Tubulin Modulators - chemical synthesis ; Tubulin Modulators - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2012-08, Vol.55 (15), p.6724-6737</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-d49a8e728d495c930ed48b18ba752a436f187c86239bb02d8fbc308b8f2ff7e73</citedby><cites>FETCH-LOGICAL-a381t-d49a8e728d495c930ed48b18ba752a436f187c86239bb02d8fbc308b8f2ff7e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm2017573$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm2017573$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22607205$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abad, Andrés</creatorcontrib><creatorcontrib>López-Pérez, José L</creatorcontrib><creatorcontrib>del Olmo, Esther</creatorcontrib><creatorcontrib>García-Fernández, Luis F</creatorcontrib><creatorcontrib>Francesch, Andrés</creatorcontrib><creatorcontrib>Trigili, Chiara</creatorcontrib><creatorcontrib>Barasoain, Isabel</creatorcontrib><creatorcontrib>Andreu, José M</creatorcontrib><creatorcontrib>Díaz, J. Fernando</creatorcontrib><creatorcontrib>San Feliciano, Arturo</creatorcontrib><title>Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.</description><subject>Antimitotic Agents - chemical synthesis</subject><subject>Antimitotic Agents - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Binding, Competitive</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Microtubules - drug effects</subject><subject>Microtubules - ultrastructure</subject><subject>Models, Molecular</subject><subject>Podophyllotoxin - analogs & derivatives</subject><subject>Podophyllotoxin - chemical synthesis</subject><subject>Podophyllotoxin - pharmacology</subject><subject>Stereoisomerism</subject><subject>Tubulin Modulators - chemical synthesis</subject><subject>Tubulin Modulators - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1LAzEQhoMotlYP_gHZi6CH1WSy202PpX5C0YL1vGSzCU3NJjXJFvvvXW3tydPMMA8vvA9C5wTfEAzkdtkAJkVe0APUJzngNGM4O0R9jAFSGALtoZMQlhhjSoAeox7AEBeA8z76eNvYuJBBh4TbOhnbqBsdXdTi9563VWu0TZ5tlJ6LqJ1NZt4pbWRInEpe3FqaZKYtF84kd9LrNY96vX3OXO1Wi40xLrovbcMpOlLcBHm2mwP0_nA_nzyl09fH58l4mnLKSEzrbMSZLIB1Sy5GFMs6YxVhFS9y4BkdKsIKwbpao6rCUDNVCYpZxRQoVciCDtDVNnfl3WcrQywbHYQ0hlvp2lASTCnJ6RCgQ6-3qPAuBC9VufK64X7TQeWP23LvtmMvdrFt1ch6T_7J7IDLLcBFKJeu9bZr-U_QN1zrgPU</recordid><startdate>20120809</startdate><enddate>20120809</enddate><creator>Abad, Andrés</creator><creator>López-Pérez, José L</creator><creator>del Olmo, Esther</creator><creator>García-Fernández, Luis F</creator><creator>Francesch, Andrés</creator><creator>Trigili, Chiara</creator><creator>Barasoain, Isabel</creator><creator>Andreu, José M</creator><creator>Díaz, J. Fernando</creator><creator>San Feliciano, Arturo</creator><general>American Chemical Society</general><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></search><sort><creationdate>20120809</creationdate><title>Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins</title><author>Abad, Andrés ; López-Pérez, José L ; del Olmo, Esther ; García-Fernández, Luis F ; Francesch, Andrés ; Trigili, Chiara ; Barasoain, Isabel ; Andreu, José M ; Díaz, J. 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Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22607205</pmid><doi>10.1021/jm2017573</doi><tpages>14</tpages></addata></record> |
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| subjects | Antimitotic Agents - chemical synthesis Antimitotic Agents - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Binding, Competitive Cell Cycle - drug effects Cell Line, Tumor Cell Proliferation Drug Screening Assays, Antitumor Humans Microtubules - drug effects Microtubules - ultrastructure Models, Molecular Podophyllotoxin - analogs & derivatives Podophyllotoxin - chemical synthesis Podophyllotoxin - pharmacology Stereoisomerism Tubulin Modulators - chemical synthesis Tubulin Modulators - pharmacology |
| title | Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins |
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