Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor
For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure–activity relationship stud...
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| Veröffentlicht in: | European journal of medicinal chemistry 2015-01, Vol.90, p.302-314 |
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| container_title | European journal of medicinal chemistry |
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| creator | Kadayat, Tara Man Park, Chanmi Jun, Kyu-Yeon Thapa Magar, Til Bahadur Bist, Ganesh Yoo, Han Young Kwon, Youngjoo Lee, Eung-Seok |
| description | For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure–activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIα (topo IIα) inhibitory activity and potent antiproliferative activity. Positive correlation between topo IIα inhibition and antiproliferative activity was observed for compounds 15, 16, 18–20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIα catalytic inhibitor.
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•2,4-Diphenyl indenopyridines were prepared for topo I and II inhibition, and antiproliferative activity.•Most indenopyridines showed selective and strong topo IIα inhibition as well as antiproliferative activity.•Positive correlation between topo IIα inhibition and antiproliferative activity was observed.•Increased number of hydroxyl moiety is important for selectivity of topo IIα inhibition.•Compound 16 was a non-intercalative topo IIα catalytic inhibitor. |
| doi_str_mv | 10.1016/j.ejmech.2014.11.046 |
| format | Article |
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•2,4-Diphenyl indenopyridines were prepared for topo I and II inhibition, and antiproliferative activity.•Most indenopyridines showed selective and strong topo IIα inhibition as well as antiproliferative activity.•Positive correlation between topo IIα inhibition and antiproliferative activity was observed.•Increased number of hydroxyl moiety is important for selectivity of topo IIα inhibition.•Compound 16 was a non-intercalative topo IIα catalytic inhibitor.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.11.046</identifier><identifier>PMID: 25437617</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Anticancer agents ; Antigens, Neoplasm - metabolism ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antiproliferative activity ; Biocatalysis ; Cell Line, Tumor ; Cell Proliferation - drug effects ; DNA Topoisomerases, Type II - metabolism ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HeLa Cells ; Humans ; Hydroxylated 2,4-diphenyl indenopyridine ; Hydroxylation ; Indenes - chemical synthesis ; Indenes - chemistry ; Indenes - pharmacology ; Molecular Structure ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Structure-Activity Relationship ; Terpyridine ; Topoisomerase II Inhibitors - chemical synthesis ; Topoisomerase II Inhibitors - chemistry ; Topoisomerase II Inhibitors - pharmacology ; Topoisomerase IIα non-intercalative catalytic inhibitor</subject><ispartof>European journal of medicinal chemistry, 2015-01, Vol.90, p.302-314</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-c292t-8ead62800a1373564b5e6753fc194bc03dc8e6ceb4835ac6bafc8a49f17aa8ff3</citedby><cites>FETCH-LOGICAL-c292t-8ead62800a1373564b5e6753fc194bc03dc8e6ceb4835ac6bafc8a49f17aa8ff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523414010782$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25437617$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kadayat, Tara Man</creatorcontrib><creatorcontrib>Park, Chanmi</creatorcontrib><creatorcontrib>Jun, Kyu-Yeon</creatorcontrib><creatorcontrib>Thapa Magar, Til Bahadur</creatorcontrib><creatorcontrib>Bist, Ganesh</creatorcontrib><creatorcontrib>Yoo, Han Young</creatorcontrib><creatorcontrib>Kwon, Youngjoo</creatorcontrib><creatorcontrib>Lee, Eung-Seok</creatorcontrib><title>Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure–activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIα (topo IIα) inhibitory activity and potent antiproliferative activity. Positive correlation between topo IIα inhibition and antiproliferative activity was observed for compounds 15, 16, 18–20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIα catalytic inhibitor.
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•2,4-Diphenyl indenopyridines were prepared for topo I and II inhibition, and antiproliferative activity.•Most indenopyridines showed selective and strong topo IIα inhibition as well as antiproliferative activity.•Positive correlation between topo IIα inhibition and antiproliferative activity was observed.•Increased number of hydroxyl moiety is important for selectivity of topo IIα inhibition.•Compound 16 was a non-intercalative topo IIα catalytic inhibitor.</description><subject>Anticancer agents</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antiproliferative activity</subject><subject>Biocatalysis</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>DNA Topoisomerases, Type II - metabolism</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hydroxylated 2,4-diphenyl indenopyridine</subject><subject>Hydroxylation</subject><subject>Indenes - chemical synthesis</subject><subject>Indenes - chemistry</subject><subject>Indenes - pharmacology</subject><subject>Molecular Structure</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Terpyridine</subject><subject>Topoisomerase II Inhibitors - chemical synthesis</subject><subject>Topoisomerase II Inhibitors - chemistry</subject><subject>Topoisomerase II Inhibitors - pharmacology</subject><subject>Topoisomerase IIα non-intercalative catalytic inhibitor</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>eNp9kM1q3DAQgEVJaTZp36AUHXOoXf1Z9l4CJbTJQqCX9ixkacxqsSVH0i419KXyIn2marNJjoWBYZhvZpgPoY-U1JRQ-WVXw24Cs60ZoaKmtCZCvkEr2squ4qwRZ2hFGONVw7g4Rxcp7QghjSTkHTovbd5K2q7Qn7vFxvB7GXUGi9lnUVk3b8EvI3begg_zEp11HrCF6A46uwMkrEvgBCOYY4198JXzGaLR4xOBc5iDS2GCqBPgzebvIzY663HJzpTFW9e7HOJ79HbQY4IPz_kS_fr-7efNXXX_43Zz8_W-MmzNctWBtpJ1hGjKW95I0Tcg24YPhq5Fbwi3pgNpoBcdb7SRvR5Mp8V6oK3W3TDwS3R12jvH8LCHlNXkkoFx1B7CPikqRbFExZoXVJxQE0NKEQY1RzfpuChK1NG72qmTd3X0rihVxXsZ-_R8Yd9PYF-HXkQX4PoEQPnz4CCqZBx4A9bFYlHZ4P5_4R9lmJnf</recordid><startdate>20150127</startdate><enddate>20150127</enddate><creator>Kadayat, Tara Man</creator><creator>Park, Chanmi</creator><creator>Jun, Kyu-Yeon</creator><creator>Thapa Magar, Til Bahadur</creator><creator>Bist, Ganesh</creator><creator>Yoo, Han Young</creator><creator>Kwon, Youngjoo</creator><creator>Lee, Eung-Seok</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>20150127</creationdate><title>Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor</title><author>Kadayat, Tara Man ; Park, Chanmi ; Jun, Kyu-Yeon ; Thapa Magar, Til Bahadur ; Bist, Ganesh ; Yoo, Han Young ; Kwon, Youngjoo ; Lee, Eung-Seok</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c292t-8ead62800a1373564b5e6753fc194bc03dc8e6ceb4835ac6bafc8a49f17aa8ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Anticancer agents</topic><topic>Antigens, Neoplasm - metabolism</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antiproliferative activity</topic><topic>Biocatalysis</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>DNA Topoisomerases, Type II - metabolism</topic><topic>DNA-Binding Proteins - antagonists & inhibitors</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Hydroxylated 2,4-diphenyl indenopyridine</topic><topic>Hydroxylation</topic><topic>Indenes - chemical synthesis</topic><topic>Indenes - chemistry</topic><topic>Indenes - pharmacology</topic><topic>Molecular Structure</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Terpyridine</topic><topic>Topoisomerase II Inhibitors - chemical synthesis</topic><topic>Topoisomerase II Inhibitors - chemistry</topic><topic>Topoisomerase II Inhibitors - pharmacology</topic><topic>Topoisomerase IIα non-intercalative catalytic inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kadayat, Tara Man</creatorcontrib><creatorcontrib>Park, Chanmi</creatorcontrib><creatorcontrib>Jun, Kyu-Yeon</creatorcontrib><creatorcontrib>Thapa Magar, Til Bahadur</creatorcontrib><creatorcontrib>Bist, Ganesh</creatorcontrib><creatorcontrib>Yoo, Han Young</creatorcontrib><creatorcontrib>Kwon, Youngjoo</creatorcontrib><creatorcontrib>Lee, Eung-Seok</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>Kadayat, Tara Man</au><au>Park, Chanmi</au><au>Jun, Kyu-Yeon</au><au>Thapa Magar, Til Bahadur</au><au>Bist, Ganesh</au><au>Yoo, Han Young</au><au>Kwon, Youngjoo</au><au>Lee, Eung-Seok</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2015-01-27</date><risdate>2015</risdate><volume>90</volume><spage>302</spage><epage>314</epage><pages>302-314</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure–activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIα (topo IIα) inhibitory activity and potent antiproliferative activity. Positive correlation between topo IIα inhibition and antiproliferative activity was observed for compounds 15, 16, 18–20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIα catalytic inhibitor.
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•2,4-Diphenyl indenopyridines were prepared for topo I and II inhibition, and antiproliferative activity.•Most indenopyridines showed selective and strong topo IIα inhibition as well as antiproliferative activity.•Positive correlation between topo IIα inhibition and antiproliferative activity was observed.•Increased number of hydroxyl moiety is important for selectivity of topo IIα inhibition.•Compound 16 was a non-intercalative topo IIα catalytic inhibitor.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>25437617</pmid><doi>10.1016/j.ejmech.2014.11.046</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | European journal of medicinal chemistry, 2015-01, Vol.90, p.302-314 |
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| subjects | Anticancer agents Antigens, Neoplasm - metabolism Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antiproliferative activity Biocatalysis Cell Line, Tumor Cell Proliferation - drug effects DNA Topoisomerases, Type II - metabolism DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Drug Screening Assays, Antitumor HeLa Cells Humans Hydroxylated 2,4-diphenyl indenopyridine Hydroxylation Indenes - chemical synthesis Indenes - chemistry Indenes - pharmacology Molecular Structure Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Structure-Activity Relationship Terpyridine Topoisomerase II Inhibitors - chemical synthesis Topoisomerase II Inhibitors - chemistry Topoisomerase II Inhibitors - pharmacology Topoisomerase IIα non-intercalative catalytic inhibitor |
| title | Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor |
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