Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells
Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1–58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2016-09, Vol.59 (17), p.7974-7990 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 7990 |
|---|---|
| container_issue | 17 |
| container_start_page | 7974 |
| container_title | Journal of medicinal chemistry |
| container_volume | 59 |
| creator | Liao, Yi Niu, Xiaojia Chen, Bailing Edwards, Holly Xu, Liping Xie, Chengzhi Lin, Hai Polin, Lisa Taub, Jeffrey W Ge, Yubin Qin, Zhihui |
| description | Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1–58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1–58 yielded 3–35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7–C8 olefin of PL obtained 3–31/3–98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro-survival proteins, and inducing expression of pro-apoptotic proteins. |
| doi_str_mv | 10.1021/acs.jmedchem.6b00772 |
| format | Article |
| fullrecord | <record><control><sourceid>acs_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6878111</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>i50367532</sourcerecordid><originalsourceid>FETCH-LOGICAL-a449t-762f6da557ad27291dae759b5c895c11cd9c371b2640cad879d7861222f323f03</originalsourceid><addsrcrecordid>eNp9kd1KwzAYhoMoOqd3IJIb6Ey-_qQ9Ecb82WCioB6HNEm3aJuOJJ3s7u02FT3xKAff-zyB90XogpIRJUCvhPSjt0YrudTNKCsJYQwO0ICmQKIkJ8khGhACEEEG8Qk69f6NEBJTiI_RCbCUpHmSD9DH88aGpfbGY2EVHttgat2968ZIPJbBrE0w2uO2wk9mpV3d2kXXGKt36enNeIJndmlKE1qHp5vSGdWLFsJYH3q-Cxo_bHTdGoXne63AE13X_gwdVaL2-vzrHaLXu9uXyTSaP97PJuN5JJKkCBHLoMqUSFMmFDAoqBKapUWZyrxIJaVSFTJmtIQsIVKonBWK5RkFgCqGuCLxEF3vvauu3JalbXCi5itnGuE2vBWG_71Ys-SLds2znOWU0l6Q7AXStd47Xf2wlPDtELwfgn8Pwb-G6LHL3__-QN_N9wGyD-zwtnO2r-F_5yeRqZq6</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells</title><source>ACS Publications</source><source>MEDLINE</source><creator>Liao, Yi ; Niu, Xiaojia ; Chen, Bailing ; Edwards, Holly ; Xu, Liping ; Xie, Chengzhi ; Lin, Hai ; Polin, Lisa ; Taub, Jeffrey W ; Ge, Yubin ; Qin, Zhihui</creator><creatorcontrib>Liao, Yi ; Niu, Xiaojia ; Chen, Bailing ; Edwards, Holly ; Xu, Liping ; Xie, Chengzhi ; Lin, Hai ; Polin, Lisa ; Taub, Jeffrey W ; Ge, Yubin ; Qin, Zhihui</creatorcontrib><description>Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1–58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1–58 yielded 3–35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7–C8 olefin of PL obtained 3–31/3–98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro-survival proteins, and inducing expression of pro-apoptotic proteins.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b00772</identifier><identifier>PMID: 27505848</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis Regulatory Proteins - metabolism ; Cell Line, Tumor ; Dioxolanes - chemical synthesis ; Dioxolanes - chemistry ; Dioxolanes - pharmacology ; DNA Repair ; Drug Screening Assays, Antitumor ; Glutathione - metabolism ; Histone Deacetylase Inhibitors - chemical synthesis ; Histone Deacetylase Inhibitors - chemistry ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Hydroxamic Acids - chemical synthesis ; Hydroxamic Acids - chemistry ; Hydroxamic Acids - pharmacology ; Leukemia, Myeloid, Acute ; Structure-Activity Relationship ; Vorinostat</subject><ispartof>Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7974-7990</ispartof><rights>Copyright © 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-762f6da557ad27291dae759b5c895c11cd9c371b2640cad879d7861222f323f03</citedby><cites>FETCH-LOGICAL-a449t-762f6da557ad27291dae759b5c895c11cd9c371b2640cad879d7861222f323f03</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/acs.jmedchem.6b00772$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00772$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27505848$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Yi</creatorcontrib><creatorcontrib>Niu, Xiaojia</creatorcontrib><creatorcontrib>Chen, Bailing</creatorcontrib><creatorcontrib>Edwards, Holly</creatorcontrib><creatorcontrib>Xu, Liping</creatorcontrib><creatorcontrib>Xie, Chengzhi</creatorcontrib><creatorcontrib>Lin, Hai</creatorcontrib><creatorcontrib>Polin, Lisa</creatorcontrib><creatorcontrib>Taub, Jeffrey W</creatorcontrib><creatorcontrib>Ge, Yubin</creatorcontrib><creatorcontrib>Qin, Zhihui</creatorcontrib><title>Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1–58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1–58 yielded 3–35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7–C8 olefin of PL obtained 3–31/3–98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro-survival proteins, and inducing expression of pro-apoptotic proteins.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Dioxolanes - chemical synthesis</subject><subject>Dioxolanes - chemistry</subject><subject>Dioxolanes - pharmacology</subject><subject>DNA Repair</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Glutathione - metabolism</subject><subject>Histone Deacetylase Inhibitors - chemical synthesis</subject><subject>Histone Deacetylase Inhibitors - chemistry</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydroxamic Acids - chemical synthesis</subject><subject>Hydroxamic Acids - chemistry</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Leukemia, Myeloid, Acute</subject><subject>Structure-Activity Relationship</subject><subject>Vorinostat</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd1KwzAYhoMoOqd3IJIb6Ey-_qQ9Ecb82WCioB6HNEm3aJuOJJ3s7u02FT3xKAff-zyB90XogpIRJUCvhPSjt0YrudTNKCsJYQwO0ICmQKIkJ8khGhACEEEG8Qk69f6NEBJTiI_RCbCUpHmSD9DH88aGpfbGY2EVHttgat2968ZIPJbBrE0w2uO2wk9mpV3d2kXXGKt36enNeIJndmlKE1qHp5vSGdWLFsJYH3q-Cxo_bHTdGoXne63AE13X_gwdVaL2-vzrHaLXu9uXyTSaP97PJuN5JJKkCBHLoMqUSFMmFDAoqBKapUWZyrxIJaVSFTJmtIQsIVKonBWK5RkFgCqGuCLxEF3vvauu3JalbXCi5itnGuE2vBWG_71Ys-SLds2znOWU0l6Q7AXStd47Xf2wlPDtELwfgn8Pwb-G6LHL3__-QN_N9wGyD-zwtnO2r-F_5yeRqZq6</recordid><startdate>20160908</startdate><enddate>20160908</enddate><creator>Liao, Yi</creator><creator>Niu, Xiaojia</creator><creator>Chen, Bailing</creator><creator>Edwards, Holly</creator><creator>Xu, Liping</creator><creator>Xie, Chengzhi</creator><creator>Lin, Hai</creator><creator>Polin, Lisa</creator><creator>Taub, Jeffrey W</creator><creator>Ge, Yubin</creator><creator>Qin, Zhihui</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>5PM</scope></search><sort><creationdate>20160908</creationdate><title>Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells</title><author>Liao, Yi ; Niu, Xiaojia ; Chen, Bailing ; Edwards, Holly ; Xu, Liping ; Xie, Chengzhi ; Lin, Hai ; Polin, Lisa ; Taub, Jeffrey W ; Ge, Yubin ; Qin, Zhihui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-762f6da557ad27291dae759b5c895c11cd9c371b2640cad879d7861222f323f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Dioxolanes - chemical synthesis</topic><topic>Dioxolanes - chemistry</topic><topic>Dioxolanes - pharmacology</topic><topic>DNA Repair</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Glutathione - metabolism</topic><topic>Histone Deacetylase Inhibitors - chemical synthesis</topic><topic>Histone Deacetylase Inhibitors - chemistry</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydroxamic Acids - chemical synthesis</topic><topic>Hydroxamic Acids - chemistry</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Leukemia, Myeloid, Acute</topic><topic>Structure-Activity Relationship</topic><topic>Vorinostat</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liao, Yi</creatorcontrib><creatorcontrib>Niu, Xiaojia</creatorcontrib><creatorcontrib>Chen, Bailing</creatorcontrib><creatorcontrib>Edwards, Holly</creatorcontrib><creatorcontrib>Xu, Liping</creatorcontrib><creatorcontrib>Xie, Chengzhi</creatorcontrib><creatorcontrib>Lin, Hai</creatorcontrib><creatorcontrib>Polin, Lisa</creatorcontrib><creatorcontrib>Taub, Jeffrey W</creatorcontrib><creatorcontrib>Ge, Yubin</creatorcontrib><creatorcontrib>Qin, Zhihui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liao, Yi</au><au>Niu, Xiaojia</au><au>Chen, Bailing</au><au>Edwards, Holly</au><au>Xu, Liping</au><au>Xie, Chengzhi</au><au>Lin, Hai</au><au>Polin, Lisa</au><au>Taub, Jeffrey W</au><au>Ge, Yubin</au><au>Qin, Zhihui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-09-08</date><risdate>2016</risdate><volume>59</volume><issue>17</issue><spage>7974</spage><epage>7990</epage><pages>7974-7990</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1–58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1–58 yielded 3–35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7–C8 olefin of PL obtained 3–31/3–98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro-survival proteins, and inducing expression of pro-apoptotic proteins.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27505848</pmid><doi>10.1021/acs.jmedchem.6b00772</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7974-7990 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6878111 |
| source | ACS Publications; MEDLINE |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Regulatory Proteins - metabolism Cell Line, Tumor Dioxolanes - chemical synthesis Dioxolanes - chemistry Dioxolanes - pharmacology DNA Repair Drug Screening Assays, Antitumor Glutathione - metabolism Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Leukemia, Myeloid, Acute Structure-Activity Relationship Vorinostat |
| title | Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T21%3A44%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis%20and%20Antileukemic%20Activities%20of%20Piperlongumine%20and%20HDAC%20Inhibitor%20Hybrids%20against%20Acute%20Myeloid%20Leukemia%20Cells&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Liao,%20Yi&rft.date=2016-09-08&rft.volume=59&rft.issue=17&rft.spage=7974&rft.epage=7990&rft.pages=7974-7990&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.6b00772&rft_dat=%3Cacs_pubme%3Ei50367532%3C/acs_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/27505848&rfr_iscdi=true |