Investigation of podophyllotoxin esters as potential anticancer agents: Synthesis, biological studies and tubulin inhibition properties
A series of fifteen podophyllotoxin derived esters have been synthesized and their anti-cancer properties have been evaluated against A549 (lung cancer), DU-145 (prostate cancer), HepG2 (liver cancer), HeLa (cervical cancer) and MCF-7 (breast cancer) cell lines. Five compounds of the series 8a, 8g–h...
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| Veröffentlicht in: | European journal of medicinal chemistry 2015-01, Vol.89, p.128-137 |
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| creator | Shareef, Mohd Adil Duscharla, Divya Ramasatyaveni, G. Dhoke, Neha R. Das, Amitava Ummanni, Ramesh Srivastava, Ajay Kumar |
| description | A series of fifteen podophyllotoxin derived esters have been synthesized and their anti-cancer properties have been evaluated against A549 (lung cancer), DU-145 (prostate cancer), HepG2 (liver cancer), HeLa (cervical cancer) and MCF-7 (breast cancer) cell lines. Five compounds of the series 8a, 8g–h, 8m and 8o showed IC50 values in the range of 0.71–10.94 μM. Among compounds, 8g and 8h showed significant cytotoxicity towards all the types of cancer studied. Cell cycle analysis revealed that the compounds 8a, 8m and 8o inhibit proliferation by cell cycle arrest. Also Hoechst-positive nucleus indicating apoptosis of these cells was observed in presence of 8g–h. Further studies revealed that these compounds inhibit tubulin polymerization and leads to the inactivation of AKT/PKB that are known to play an important role in the proliferation of cancer cells.
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•A series of fifteen podophyllotoxin derivatives have been synthesized.•Five compounds of the series 8a, 8g–h, 8m and 8o showed cytotoxicity in submicromolar range.•The FACS analysis showed that the potent compounds showed cell cycle arrest in G0/G1 and sub G1phase.•The tubulin polymerization inhibition properties of the active molecules have been studied. |
| doi_str_mv | 10.1016/j.ejmech.2014.10.050 |
| format | Article |
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•A series of fifteen podophyllotoxin derivatives have been synthesized.•Five compounds of the series 8a, 8g–h, 8m and 8o showed cytotoxicity in submicromolar range.•The FACS analysis showed that the potent compounds showed cell cycle arrest in G0/G1 and sub G1phase.•The tubulin polymerization inhibition properties of the active molecules have been studied.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.10.050</identifier><identifier>PMID: 25462233</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Anticancer agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; CA-4 ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Esters - chemical synthesis ; Esters - chemistry ; Esters - pharmacology ; Hep G2 Cells ; Humans ; MCF-7 Cells ; Molecular Structure ; Podophyllotoxin ; Podophyllotoxin - analogs & derivatives ; Podophyllotoxin - chemistry ; Podophyllotoxin - pharmacology ; Structure-Activity Relationship ; Tubulin - metabolism ; Tubulin Modulators - chemical synthesis ; Tubulin Modulators - chemistry ; Tubulin Modulators - pharmacology ; Tubulin polymerization inhibition</subject><ispartof>European journal of medicinal chemistry, 2015-01, Vol.89, p.128-137</ispartof><rights>2014 Elsevier Masson SAS</rights><rights>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-33002c426cadcf0a66b06f098f108fe42769712eca218b66d3c7ba49ff5f56483</citedby><cites>FETCH-LOGICAL-c362t-33002c426cadcf0a66b06f098f108fe42769712eca218b66d3c7ba49ff5f56483</cites><orcidid>0000-0001-8463-7153</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523414009787$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25462233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shareef, Mohd Adil</creatorcontrib><creatorcontrib>Duscharla, Divya</creatorcontrib><creatorcontrib>Ramasatyaveni, G.</creatorcontrib><creatorcontrib>Dhoke, Neha R.</creatorcontrib><creatorcontrib>Das, Amitava</creatorcontrib><creatorcontrib>Ummanni, Ramesh</creatorcontrib><creatorcontrib>Srivastava, Ajay Kumar</creatorcontrib><title>Investigation of podophyllotoxin esters as potential anticancer agents: Synthesis, biological studies and tubulin inhibition properties</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A series of fifteen podophyllotoxin derived esters have been synthesized and their anti-cancer properties have been evaluated against A549 (lung cancer), DU-145 (prostate cancer), HepG2 (liver cancer), HeLa (cervical cancer) and MCF-7 (breast cancer) cell lines. Five compounds of the series 8a, 8g–h, 8m and 8o showed IC50 values in the range of 0.71–10.94 μM. Among compounds, 8g and 8h showed significant cytotoxicity towards all the types of cancer studied. Cell cycle analysis revealed that the compounds 8a, 8m and 8o inhibit proliferation by cell cycle arrest. Also Hoechst-positive nucleus indicating apoptosis of these cells was observed in presence of 8g–h. Further studies revealed that these compounds inhibit tubulin polymerization and leads to the inactivation of AKT/PKB that are known to play an important role in the proliferation of cancer cells.
[Display omitted]
•A series of fifteen podophyllotoxin derivatives have been synthesized.•Five compounds of the series 8a, 8g–h, 8m and 8o showed cytotoxicity in submicromolar range.•The FACS analysis showed that the potent compounds showed cell cycle arrest in G0/G1 and sub G1phase.•The tubulin polymerization inhibition properties of the active molecules have been studied.</description><subject>Anticancer agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>CA-4</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Esters - chemical synthesis</subject><subject>Esters - chemistry</subject><subject>Esters - pharmacology</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Molecular Structure</subject><subject>Podophyllotoxin</subject><subject>Podophyllotoxin - analogs & derivatives</subject><subject>Podophyllotoxin - chemistry</subject><subject>Podophyllotoxin - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tubulin - metabolism</subject><subject>Tubulin Modulators - chemical synthesis</subject><subject>Tubulin Modulators - chemistry</subject><subject>Tubulin Modulators - pharmacology</subject><subject>Tubulin polymerization inhibition</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1vEzEQtRCIpoV_gJCPHNjgr_VuOCBVFZRKlTgAZ8vrHSeOnPVieyvyC_jbTEjhyGmk9zFPM4-QV5ytOeP63X4N-wO43VowrhBas5Y9ISve6b6RolVPyYoJIZtWSHVBLkvZM8ZazdhzcoG0Rk6uyK-76QFKDVtbQ5po8nROY5p3xxhTTT_DRJGFXKgtyFSYarCRWhzOTg4ytVvEynv69TjVHZRQ3tIhpJi2KIi01GUMgO5ppHUZlogLw7QLQ_gTN-c0Q66oeEGeeRsLvHycV-T7p4_fbj43919u726u7xsntaiNlIwJp4R2dnSeWa0Hpj3b9J6z3oMSnd50XICzgveD1qN03WDVxvvWt1r18oq8Oe_F6B8L3mYOoTiI0U6QlmK4lqoTuu8UStVZ6nIqJYM3cw4Hm4-GM3OqwOzNuQJzquCEYgVoe_2YsAwHGP-Z_v4cBR_OAsA7HwJkU1wAfOYYMrhqxhT-n_AbneSdGw</recordid><startdate>20150107</startdate><enddate>20150107</enddate><creator>Shareef, Mohd Adil</creator><creator>Duscharla, Divya</creator><creator>Ramasatyaveni, G.</creator><creator>Dhoke, Neha R.</creator><creator>Das, Amitava</creator><creator>Ummanni, Ramesh</creator><creator>Srivastava, Ajay Kumar</creator><general>Elsevier Masson SAS</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><orcidid>https://orcid.org/0000-0001-8463-7153</orcidid></search><sort><creationdate>20150107</creationdate><title>Investigation of podophyllotoxin esters as potential anticancer agents: Synthesis, biological studies and tubulin inhibition properties</title><author>Shareef, Mohd Adil ; Duscharla, Divya ; Ramasatyaveni, G. ; Dhoke, Neha R. ; Das, Amitava ; Ummanni, Ramesh ; Srivastava, Ajay Kumar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-33002c426cadcf0a66b06f098f108fe42769712eca218b66d3c7ba49ff5f56483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Anticancer agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>CA-4</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Esters - chemical synthesis</topic><topic>Esters - chemistry</topic><topic>Esters - pharmacology</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>MCF-7 Cells</topic><topic>Molecular Structure</topic><topic>Podophyllotoxin</topic><topic>Podophyllotoxin - analogs & derivatives</topic><topic>Podophyllotoxin - chemistry</topic><topic>Podophyllotoxin - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tubulin - metabolism</topic><topic>Tubulin Modulators - chemical synthesis</topic><topic>Tubulin Modulators - chemistry</topic><topic>Tubulin Modulators - pharmacology</topic><topic>Tubulin polymerization inhibition</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shareef, Mohd Adil</creatorcontrib><creatorcontrib>Duscharla, Divya</creatorcontrib><creatorcontrib>Ramasatyaveni, G.</creatorcontrib><creatorcontrib>Dhoke, Neha R.</creatorcontrib><creatorcontrib>Das, Amitava</creatorcontrib><creatorcontrib>Ummanni, Ramesh</creatorcontrib><creatorcontrib>Srivastava, Ajay Kumar</creatorcontrib><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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shareef, Mohd Adil</au><au>Duscharla, Divya</au><au>Ramasatyaveni, G.</au><au>Dhoke, Neha R.</au><au>Das, Amitava</au><au>Ummanni, Ramesh</au><au>Srivastava, Ajay Kumar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Investigation of podophyllotoxin esters as potential anticancer agents: Synthesis, biological studies and tubulin inhibition properties</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2015-01-07</date><risdate>2015</risdate><volume>89</volume><spage>128</spage><epage>137</epage><pages>128-137</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>A series of fifteen podophyllotoxin derived esters have been synthesized and their anti-cancer properties have been evaluated against A549 (lung cancer), DU-145 (prostate cancer), HepG2 (liver cancer), HeLa (cervical cancer) and MCF-7 (breast cancer) cell lines. Five compounds of the series 8a, 8g–h, 8m and 8o showed IC50 values in the range of 0.71–10.94 μM. Among compounds, 8g and 8h showed significant cytotoxicity towards all the types of cancer studied. Cell cycle analysis revealed that the compounds 8a, 8m and 8o inhibit proliferation by cell cycle arrest. Also Hoechst-positive nucleus indicating apoptosis of these cells was observed in presence of 8g–h. Further studies revealed that these compounds inhibit tubulin polymerization and leads to the inactivation of AKT/PKB that are known to play an important role in the proliferation of cancer cells.
[Display omitted]
•A series of fifteen podophyllotoxin derivatives have been synthesized.•Five compounds of the series 8a, 8g–h, 8m and 8o showed cytotoxicity in submicromolar range.•The FACS analysis showed that the potent compounds showed cell cycle arrest in G0/G1 and sub G1phase.•The tubulin polymerization inhibition properties of the active molecules have been studied.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>25462233</pmid><doi>10.1016/j.ejmech.2014.10.050</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-8463-7153</orcidid></addata></record> |
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| subjects | Anticancer agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects CA-4 Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Esters - chemical synthesis Esters - chemistry Esters - pharmacology Hep G2 Cells Humans MCF-7 Cells Molecular Structure Podophyllotoxin Podophyllotoxin - analogs & derivatives Podophyllotoxin - chemistry Podophyllotoxin - pharmacology Structure-Activity Relationship Tubulin - metabolism Tubulin Modulators - chemical synthesis Tubulin Modulators - chemistry Tubulin Modulators - pharmacology Tubulin polymerization inhibition |
| title | Investigation of podophyllotoxin esters as potential anticancer agents: Synthesis, biological studies and tubulin inhibition properties |
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