Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells

In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:European journal of medicinal chemistry 2021-10, Vol.221, p.113489-113489, Article 113489
Hauptverfasser: İbiş, Kübra, Nalbat, Esra, Çalışkan, Burcu, Kahraman, Deniz Cansen, Cetin-Atalay, Rengul, Banoglu, Erden
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 113489
container_issue
container_start_page 113489
container_title European journal of medicinal chemistry
container_volume 221
creator İbiş, Kübra
Nalbat, Esra
Çalışkan, Burcu
Kahraman, Deniz Cansen
Cetin-Atalay, Rengul
Banoglu, Erden
description In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC50 values in the range of 0.09–11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties. [Display omitted] •Synthesis of novel isoxazole-piperazine derivatives as anti-cancer agents is reported.•Compounds are evaluated against Huh7, Mahlavu and MCF7 cancer cell lines.•Compounds showed cytotoxicity with IC50 values in the range of 0.09–11.7 μM.•Compounds caused a decrease in cancer stem cell population.
doi_str_mv 10.1016/j.ejmech.2021.113489
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2522617063</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S022352342100338X</els_id><sourcerecordid>2522617063</sourcerecordid><originalsourceid>FETCH-LOGICAL-c362t-f907b703141ab3ebf72a2b56bdf33702e9948c849f529b4a215e738a9dafbaf73</originalsourceid><addsrcrecordid>eNp9kctuFDEQRS1ERIbAHyDkJZse_OjnBglFPCJFYkGytmx3OV2j7nZje4ZMfoWfjUc9sGRVknVulasOIe8423LG64-7LewmsMNWMMG3nMuy7V6QDW_qtpCiKl-SDRNCFpWQ5SV5HeOOMVbVjL0il1J2Fa_KbkP-_DzOaYCIkeq5pwb96B_Q6pHCQY97ndDP1Ds6-wOMFKN_1E9-hGLBBYJ-whnocDQB-5yPdPEJ5oQ5rXMprJ4tBKof8mOkvzENFOcBDSYfjhScA5to7j_iIWNnOiaYqIVxjG_IhdNjhLfnekXuv365u_5e3P74dnP9-bawshapcB1rTMMkL7k2EoxrhBamqk3vpGyYgK4rW9uWnatEZ0oteAWNbHXXa2e0a-QV-bD2XYL_tYeY1ITx9AM9g99HJSohat6wWma0XFEbfIwBnFoCTjocFWfqpEXt1KpFnbSoVUuOvT9P2JsJ-n-hvx4y8GkFIO95QAgqWoR8jx5DPpLqPf5_wjNxpaQg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2522617063</pqid></control><display><type>article</type><title>Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells</title><source>Elsevier ScienceDirect Journals Complete</source><creator>İbiş, Kübra ; Nalbat, Esra ; Çalışkan, Burcu ; Kahraman, Deniz Cansen ; Cetin-Atalay, Rengul ; Banoglu, Erden</creator><creatorcontrib>İbiş, Kübra ; Nalbat, Esra ; Çalışkan, Burcu ; Kahraman, Deniz Cansen ; Cetin-Atalay, Rengul ; Banoglu, Erden</creatorcontrib><description>In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC50 values in the range of 0.09–11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties. [Display omitted] •Synthesis of novel isoxazole-piperazine derivatives as anti-cancer agents is reported.•Compounds are evaluated against Huh7, Mahlavu and MCF7 cancer cell lines.•Compounds showed cytotoxicity with IC50 values in the range of 0.09–11.7 μM.•Compounds caused a decrease in cancer stem cell population.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2021.113489</identifier><identifier>PMID: 33951549</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Cancer ; Cancer stem cell ; Isoxazole ; Liver ; Piperazine</subject><ispartof>European journal of medicinal chemistry, 2021-10, Vol.221, p.113489-113489, Article 113489</ispartof><rights>2021 Elsevier Masson SAS</rights><rights>Copyright © 2021 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-f907b703141ab3ebf72a2b56bdf33702e9948c849f529b4a215e738a9dafbaf73</citedby><cites>FETCH-LOGICAL-c362t-f907b703141ab3ebf72a2b56bdf33702e9948c849f529b4a215e738a9dafbaf73</cites><orcidid>0000-0002-4051-9793 ; 0000-0002-3381-5463 ; 0000-0003-4737-1733</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2021.113489$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33951549$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>İbiş, Kübra</creatorcontrib><creatorcontrib>Nalbat, Esra</creatorcontrib><creatorcontrib>Çalışkan, Burcu</creatorcontrib><creatorcontrib>Kahraman, Deniz Cansen</creatorcontrib><creatorcontrib>Cetin-Atalay, Rengul</creatorcontrib><creatorcontrib>Banoglu, Erden</creatorcontrib><title>Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC50 values in the range of 0.09–11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties. [Display omitted] •Synthesis of novel isoxazole-piperazine derivatives as anti-cancer agents is reported.•Compounds are evaluated against Huh7, Mahlavu and MCF7 cancer cell lines.•Compounds showed cytotoxicity with IC50 values in the range of 0.09–11.7 μM.•Compounds caused a decrease in cancer stem cell population.</description><subject>Cancer</subject><subject>Cancer stem cell</subject><subject>Isoxazole</subject><subject>Liver</subject><subject>Piperazine</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kctuFDEQRS1ERIbAHyDkJZse_OjnBglFPCJFYkGytmx3OV2j7nZje4ZMfoWfjUc9sGRVknVulasOIe8423LG64-7LewmsMNWMMG3nMuy7V6QDW_qtpCiKl-SDRNCFpWQ5SV5HeOOMVbVjL0il1J2Fa_KbkP-_DzOaYCIkeq5pwb96B_Q6pHCQY97ndDP1Ds6-wOMFKN_1E9-hGLBBYJ-whnocDQB-5yPdPEJ5oQ5rXMprJ4tBKof8mOkvzENFOcBDSYfjhScA5to7j_iIWNnOiaYqIVxjG_IhdNjhLfnekXuv365u_5e3P74dnP9-bawshapcB1rTMMkL7k2EoxrhBamqk3vpGyYgK4rW9uWnatEZ0oteAWNbHXXa2e0a-QV-bD2XYL_tYeY1ITx9AM9g99HJSohat6wWma0XFEbfIwBnFoCTjocFWfqpEXt1KpFnbSoVUuOvT9P2JsJ-n-hvx4y8GkFIO95QAgqWoR8jx5DPpLqPf5_wjNxpaQg</recordid><startdate>20211005</startdate><enddate>20211005</enddate><creator>İbiş, Kübra</creator><creator>Nalbat, Esra</creator><creator>Çalışkan, Burcu</creator><creator>Kahraman, Deniz Cansen</creator><creator>Cetin-Atalay, Rengul</creator><creator>Banoglu, Erden</creator><general>Elsevier Masson SAS</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4051-9793</orcidid><orcidid>https://orcid.org/0000-0002-3381-5463</orcidid><orcidid>https://orcid.org/0000-0003-4737-1733</orcidid></search><sort><creationdate>20211005</creationdate><title>Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells</title><author>İbiş, Kübra ; Nalbat, Esra ; Çalışkan, Burcu ; Kahraman, Deniz Cansen ; Cetin-Atalay, Rengul ; Banoglu, Erden</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-f907b703141ab3ebf72a2b56bdf33702e9948c849f529b4a215e738a9dafbaf73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Cancer</topic><topic>Cancer stem cell</topic><topic>Isoxazole</topic><topic>Liver</topic><topic>Piperazine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>İbiş, Kübra</creatorcontrib><creatorcontrib>Nalbat, Esra</creatorcontrib><creatorcontrib>Çalışkan, Burcu</creatorcontrib><creatorcontrib>Kahraman, Deniz Cansen</creatorcontrib><creatorcontrib>Cetin-Atalay, Rengul</creatorcontrib><creatorcontrib>Banoglu, Erden</creatorcontrib><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>İbiş, Kübra</au><au>Nalbat, Esra</au><au>Çalışkan, Burcu</au><au>Kahraman, Deniz Cansen</au><au>Cetin-Atalay, Rengul</au><au>Banoglu, Erden</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2021-10-05</date><risdate>2021</risdate><volume>221</volume><spage>113489</spage><epage>113489</epage><pages>113489-113489</pages><artnum>113489</artnum><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC50 values in the range of 0.09–11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties. [Display omitted] •Synthesis of novel isoxazole-piperazine derivatives as anti-cancer agents is reported.•Compounds are evaluated against Huh7, Mahlavu and MCF7 cancer cell lines.•Compounds showed cytotoxicity with IC50 values in the range of 0.09–11.7 μM.•Compounds caused a decrease in cancer stem cell population.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>33951549</pmid><doi>10.1016/j.ejmech.2021.113489</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-4051-9793</orcidid><orcidid>https://orcid.org/0000-0002-3381-5463</orcidid><orcidid>https://orcid.org/0000-0003-4737-1733</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 0223-5234
ispartof European journal of medicinal chemistry, 2021-10, Vol.221, p.113489-113489, Article 113489
issn 0223-5234
1768-3254
language eng
recordid cdi_proquest_miscellaneous_2522617063
source Elsevier ScienceDirect Journals Complete
subjects Cancer
Cancer stem cell
Isoxazole
Liver
Piperazine
title Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T13%3A22%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis%20and%20biological%20evaluation%20of%20novel%20isoxazole-piperazine%20hybrids%20as%20potential%20anti-cancer%20agents%20with%20inhibitory%20effect%20on%20liver%20cancer%20stem%20cells&rft.jtitle=European%20journal%20of%20medicinal%20chemistry&rft.au=%C4%B0bi%C5%9F,%20K%C3%BCbra&rft.date=2021-10-05&rft.volume=221&rft.spage=113489&rft.epage=113489&rft.pages=113489-113489&rft.artnum=113489&rft.issn=0223-5234&rft.eissn=1768-3254&rft_id=info:doi/10.1016/j.ejmech.2021.113489&rft_dat=%3Cproquest_cross%3E2522617063%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2522617063&rft_id=info:pmid/33951549&rft_els_id=S022352342100338X&rfr_iscdi=true