Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach
The present study reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a ring disjunctive-based natural product lead (RDNPL) optimization approach. All twelve compounds were tested against a panel of cancer cells (i.e. breast, prostate, pancreatic...
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| Veröffentlicht in: | European journal of medicinal chemistry 2017-06, Vol.133, p.365-378 |
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| container_title | European journal of medicinal chemistry |
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| creator | Manivannan, Elangovan Amawi, Haneen Hussein, Noor Karthikeyan, Chandrabose Fetcenko, Aubry Narayana Moorthy, N.S. Hari Trivedi, Piyush Tiwari, Amit K. |
| description | The present study reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a ring disjunctive-based natural product lead (RDNPL) optimization approach. All twelve compounds were tested against a panel of cancer cells (i.e. breast, prostate, pancreatic, and ovarian) and compared with normal cells. While all of the compounds had significantly greater efficacy than silybin, derivative 15k was found to be highly potent (IC50 |
| doi_str_mv | 10.1016/j.ejmech.2017.03.033 |
| format | Article |
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Described herein is design and synthesis of novel silybin derivatives using natural lead optimization and ring disjunctive approach leading to discovery of a lead compound 15k, which produces apoptosis in ovarian cancer cells through tubulin inhibition. [Display omitted]
•Synthesis of novel silybin derivatives by ring disjunctive natural lead optimization.•15k discovered to be highly potent and selective to ovarian cancer cells.•15k induces sub-G1cell cycle arrest and induces apoptosis.•15k binds with high affinity to tubulin and inhibit their expression.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2017.03.033</identifier><identifier>PMID: 28411546</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>(E)-3-(3-(benzyloxy)phenyl)-1-phenylprop-2-en-1-one ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemoprevention ; Crystallography, X-Ray ; Drug Screening Assays, Antitumor ; Humans ; Membrane Potential, Mitochondrial - drug effects ; Molecular Docking Simulation ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Ring disjunctive natural product lead optimization ; Silybin ; Silymarin - chemistry ; Silymarin - pharmacology ; Tubulin - chemistry ; Tubulin - metabolism ; Tubulin inhibitor ; Tubulin Modulators - chemistry ; Tubulin Modulators - pharmacology</subject><ispartof>European journal of medicinal chemistry, 2017-06, Vol.133, p.365-378</ispartof><rights>2017 Elsevier Masson SAS</rights><rights>Copyright © 2017 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-e9714f2339dbe9234cab51640b72a2be09096e63e9a17147347c1a1859e9c7ba3</citedby><cites>FETCH-LOGICAL-c362t-e9714f2339dbe9234cab51640b72a2be09096e63e9a17147347c1a1859e9c7ba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2017.03.033$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28411546$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manivannan, Elangovan</creatorcontrib><creatorcontrib>Amawi, Haneen</creatorcontrib><creatorcontrib>Hussein, Noor</creatorcontrib><creatorcontrib>Karthikeyan, Chandrabose</creatorcontrib><creatorcontrib>Fetcenko, Aubry</creatorcontrib><creatorcontrib>Narayana Moorthy, N.S. Hari</creatorcontrib><creatorcontrib>Trivedi, Piyush</creatorcontrib><creatorcontrib>Tiwari, Amit K.</creatorcontrib><title>Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>The present study reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a ring disjunctive-based natural product lead (RDNPL) optimization approach. All twelve compounds were tested against a panel of cancer cells (i.e. breast, prostate, pancreatic, and ovarian) and compared with normal cells. While all of the compounds had significantly greater efficacy than silybin, derivative 15k was found to be highly potent (IC50 < 1 μM) and selective against ovarian cancer cell lines, as well as other cancer cell lines, compared to normal cells. Preliminary mechanistic studies indicated that the antiproliferative efficacy of 15k was mediated by its induction of apoptosis, loss of mitochondrial membrane potential and cell cycle arrest at the sub-G1 phase. Furthermore, 15k inhibited cellular microtubules dynamic and assembly by binding to tubulin and inhibiting its expression and function. Overall, the results of the study establish 15k as a novel tubulin inhibitor with significant activity against ovarian cancer cells.
Described herein is design and synthesis of novel silybin derivatives using natural lead optimization and ring disjunctive approach leading to discovery of a lead compound 15k, which produces apoptosis in ovarian cancer cells through tubulin inhibition. [Display omitted]
•Synthesis of novel silybin derivatives by ring disjunctive natural lead optimization.•15k discovered to be highly potent and selective to ovarian cancer cells.•15k induces sub-G1cell cycle arrest and induces apoptosis.•15k binds with high affinity to tubulin and inhibit their expression.</description><subject>(E)-3-(3-(benzyloxy)phenyl)-1-phenylprop-2-en-1-one</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemoprevention</subject><subject>Crystallography, X-Ray</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Molecular Docking Simulation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Ring disjunctive natural product lead optimization</subject><subject>Silybin</subject><subject>Silymarin - chemistry</subject><subject>Silymarin - pharmacology</subject><subject>Tubulin - chemistry</subject><subject>Tubulin - metabolism</subject><subject>Tubulin inhibitor</subject><subject>Tubulin Modulators - chemistry</subject><subject>Tubulin Modulators - pharmacology</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcuO1DAQtBCIHRb-ACEfOZBZPxInuSCxy2ullbjA2erYnVlHiR3sZKThxD9w2P_jS_Awyx6RSupDV1epugh5ydmWM64uhi0OE5rbrWC83jKZIR-RDa9VU0hRlY_Jhgkhi0rI8ow8S2lgjFWKsafkTDQl51WpNuTuPSa38xS8pdYlE_YYDzT0NLnx0LnjAsawWzFRyPCLm2MYXY8RFrdHasI0h9XbRNfk_I4CjceRpYbVm7-U3z9_0UtIaN9QD8saYaRZw65moSOCpWFe3OR-ZL2Q7ea8A3P7nDzpYUz44n6ek28fP3y9-lzcfPl0ffXupjBSiaXAtuZlL6RsbYdtTmqgq7gqWVcLEB2ylrUKlcQWeGbWsqwNB95ULbam7kCek9cn3Wz7Padc9JS_gOMIHsOaNG-aplWcS5Gp5YlqYkgpYq_n6CaIB82ZPlaiB32qRB8r0UxmyHz26t5h7Sa0D0f_OsiEtycC5px7h1En49AbtC6iWbQN7v8OfwB2UaKw</recordid><startdate>20170616</startdate><enddate>20170616</enddate><creator>Manivannan, Elangovan</creator><creator>Amawi, Haneen</creator><creator>Hussein, Noor</creator><creator>Karthikeyan, Chandrabose</creator><creator>Fetcenko, Aubry</creator><creator>Narayana Moorthy, N.S. Hari</creator><creator>Trivedi, Piyush</creator><creator>Tiwari, Amit K.</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></search><sort><creationdate>20170616</creationdate><title>Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach</title><author>Manivannan, Elangovan ; Amawi, Haneen ; Hussein, Noor ; Karthikeyan, Chandrabose ; Fetcenko, Aubry ; Narayana Moorthy, N.S. Hari ; Trivedi, Piyush ; Tiwari, Amit K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-e9714f2339dbe9234cab51640b72a2be09096e63e9a17147347c1a1859e9c7ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>(E)-3-(3-(benzyloxy)phenyl)-1-phenylprop-2-en-1-one</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemoprevention</topic><topic>Crystallography, X-Ray</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Membrane Potential, Mitochondrial - drug effects</topic><topic>Molecular Docking Simulation</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Ring disjunctive natural product lead optimization</topic><topic>Silybin</topic><topic>Silymarin - chemistry</topic><topic>Silymarin - pharmacology</topic><topic>Tubulin - chemistry</topic><topic>Tubulin - metabolism</topic><topic>Tubulin inhibitor</topic><topic>Tubulin Modulators - chemistry</topic><topic>Tubulin Modulators - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Manivannan, Elangovan</creatorcontrib><creatorcontrib>Amawi, Haneen</creatorcontrib><creatorcontrib>Hussein, Noor</creatorcontrib><creatorcontrib>Karthikeyan, Chandrabose</creatorcontrib><creatorcontrib>Fetcenko, Aubry</creatorcontrib><creatorcontrib>Narayana Moorthy, N.S. Hari</creatorcontrib><creatorcontrib>Trivedi, Piyush</creatorcontrib><creatorcontrib>Tiwari, Amit K.</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>Manivannan, Elangovan</au><au>Amawi, Haneen</au><au>Hussein, Noor</au><au>Karthikeyan, Chandrabose</au><au>Fetcenko, Aubry</au><au>Narayana Moorthy, N.S. Hari</au><au>Trivedi, Piyush</au><au>Tiwari, Amit K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2017-06-16</date><risdate>2017</risdate><volume>133</volume><spage>365</spage><epage>378</epage><pages>365-378</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>The present study reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a ring disjunctive-based natural product lead (RDNPL) optimization approach. All twelve compounds were tested against a panel of cancer cells (i.e. breast, prostate, pancreatic, and ovarian) and compared with normal cells. While all of the compounds had significantly greater efficacy than silybin, derivative 15k was found to be highly potent (IC50 < 1 μM) and selective against ovarian cancer cell lines, as well as other cancer cell lines, compared to normal cells. Preliminary mechanistic studies indicated that the antiproliferative efficacy of 15k was mediated by its induction of apoptosis, loss of mitochondrial membrane potential and cell cycle arrest at the sub-G1 phase. Furthermore, 15k inhibited cellular microtubules dynamic and assembly by binding to tubulin and inhibiting its expression and function. Overall, the results of the study establish 15k as a novel tubulin inhibitor with significant activity against ovarian cancer cells.
Described herein is design and synthesis of novel silybin derivatives using natural lead optimization and ring disjunctive approach leading to discovery of a lead compound 15k, which produces apoptosis in ovarian cancer cells through tubulin inhibition. [Display omitted]
•Synthesis of novel silybin derivatives by ring disjunctive natural lead optimization.•15k discovered to be highly potent and selective to ovarian cancer cells.•15k induces sub-G1cell cycle arrest and induces apoptosis.•15k binds with high affinity to tubulin and inhibit their expression.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>28411546</pmid><doi>10.1016/j.ejmech.2017.03.033</doi><tpages>14</tpages></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2017-06, Vol.133, p.365-378 |
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| subjects | (E)-3-(3-(benzyloxy)phenyl)-1-phenylprop-2-en-1-one Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Line, Tumor Cell Proliferation - drug effects Chemoprevention Crystallography, X-Ray Drug Screening Assays, Antitumor Humans Membrane Potential, Mitochondrial - drug effects Molecular Docking Simulation Neoplasms - drug therapy Neoplasms - metabolism Ring disjunctive natural product lead optimization Silybin Silymarin - chemistry Silymarin - pharmacology Tubulin - chemistry Tubulin - metabolism Tubulin inhibitor Tubulin Modulators - chemistry Tubulin Modulators - pharmacology |
| title | Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach |
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