Evaluation of the DNA Alkylation Properties of a Chlorambucil‐Conjugated Cyclic Pyrrole‐Imidazole Polyamide
Hairpin pyrrole‐imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP‐Chbs) can alkylate DNA in a sequence‐specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corres...
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| Veröffentlicht in: | Chemistry : a European journal 2021-02, Vol.27 (8), p.2782-2788 |
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| creator | Hirose, Yuki Hashiya, Kaori Bando, Toshikazu Sugiyama, Hiroshi |
| description | Hairpin pyrrole‐imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP‐Chbs) can alkylate DNA in a sequence‐specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP‐Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP‐Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP‐Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP‐Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP‐Chbs could be novel DNA alkylating anticancer drugs.
Targeted alkylation: The DNA alkylation properties of a cyclic pyrrole‐imidazole polyamide that was conjugated with the DNA‐alkylator chlorambucil are reported. The conjugate shows good alkylation ability in vitro and anticancer effects against cancer cells. |
| doi_str_mv | 10.1002/chem.202004421 |
| format | Article |
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Targeted alkylation: The DNA alkylation properties of a cyclic pyrrole‐imidazole polyamide that was conjugated with the DNA‐alkylator chlorambucil are reported. The conjugate shows good alkylation ability in vitro and anticancer effects against cancer cells.</description><identifier>ISSN: 0947-6539</identifier><identifier>EISSN: 1521-3765</identifier><identifier>DOI: 10.1002/chem.202004421</identifier><identifier>PMID: 33145851</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Adenine ; Alkylates ; Alkylation ; Antifungal agents ; Antitumor agents ; Binding sites ; Cancer ; Capillary electrophoresis ; Chemistry ; Chlorambucil ; Chlorambucil - chemistry ; Conjugates ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA - chemistry ; DNA alkylator ; DNA recognition ; drug delivery ; Drugs ; Electrophoresis ; High-performance liquid chromatography ; Imidazole ; Imidazoles - chemistry ; Liquid chromatography ; Nucleotide sequence ; Nylons - chemistry ; Polyamide resins ; Polyamides ; Prostate cancer ; Pyrroles - chemistry ; Toxicity</subject><ispartof>Chemistry : a European journal, 2021-02, Vol.27 (8), p.2782-2788</ispartof><rights>2020 Wiley‐VCH GmbH</rights><rights>2020 Wiley-VCH GmbH.</rights><rights>2021 Wiley‐VCH GmbH</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4941-3969d38f99f71cc7d37e2b3e835d722606a0e67a7e69a609f88f40f4c51aac6d3</citedby><cites>FETCH-LOGICAL-c4941-3969d38f99f71cc7d37e2b3e835d722606a0e67a7e69a609f88f40f4c51aac6d3</cites><orcidid>0000-0001-8923-5946</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fchem.202004421$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fchem.202004421$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33145851$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hirose, Yuki</creatorcontrib><creatorcontrib>Hashiya, Kaori</creatorcontrib><creatorcontrib>Bando, Toshikazu</creatorcontrib><creatorcontrib>Sugiyama, Hiroshi</creatorcontrib><title>Evaluation of the DNA Alkylation Properties of a Chlorambucil‐Conjugated Cyclic Pyrrole‐Imidazole Polyamide</title><title>Chemistry : a European journal</title><addtitle>Chemistry</addtitle><description>Hairpin pyrrole‐imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP‐Chbs) can alkylate DNA in a sequence‐specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP‐Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP‐Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP‐Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP‐Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP‐Chbs could be novel DNA alkylating anticancer drugs.
Targeted alkylation: The DNA alkylation properties of a cyclic pyrrole‐imidazole polyamide that was conjugated with the DNA‐alkylator chlorambucil are reported. The conjugate shows good alkylation ability in vitro and anticancer effects against cancer cells.</description><subject>Adenine</subject><subject>Alkylates</subject><subject>Alkylation</subject><subject>Antifungal agents</subject><subject>Antitumor agents</subject><subject>Binding sites</subject><subject>Cancer</subject><subject>Capillary electrophoresis</subject><subject>Chemistry</subject><subject>Chlorambucil</subject><subject>Chlorambucil - chemistry</subject><subject>Conjugates</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - chemistry</subject><subject>DNA alkylator</subject><subject>DNA recognition</subject><subject>drug delivery</subject><subject>Drugs</subject><subject>Electrophoresis</subject><subject>High-performance liquid chromatography</subject><subject>Imidazole</subject><subject>Imidazoles - chemistry</subject><subject>Liquid chromatography</subject><subject>Nucleotide sequence</subject><subject>Nylons - chemistry</subject><subject>Polyamide resins</subject><subject>Polyamides</subject><subject>Prostate cancer</subject><subject>Pyrroles - chemistry</subject><subject>Toxicity</subject><issn>0947-6539</issn><issn>1521-3765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkLtOwzAUhi0EoqWwMqJIzCm-xY7HKhRaqUAHmCPXsWmKUxcnAYWJR-AZeRJSpZSR6dy-8x-dH4BzBIcIQnyllroYYoghpBSjA9BHEUYh4Sw6BH0oKA9ZREQPnJTlCkIoGCHHoEcIolEcoT5w4zdpa1nlbh04E1RLHVzfj4KRfWls1517t9G-ynW5BWSQLK3zsljUKrffn1-JW6_qZ1npLEgaZXMVzBvvndXtbFrkmfxo82DubCPbSp-CIyNtqc92cQCebsaPySScPdxOk9EsVFTQ9gHBREZiI4ThSCmeEa7xguiYRBnHmEEmoWZccs2EZFCYODYUGqoiJKViGRmAy053491rrcsqXbnar9uTKaYxo0hEMW-pYUcp78rSa5NufF5I36QIplt_062_6d7fduFiJ1svCp3t8V9DW0B0wHtudfOPXJpMxnd_4j9zzol1</recordid><startdate>20210205</startdate><enddate>20210205</enddate><creator>Hirose, Yuki</creator><creator>Hashiya, Kaori</creator><creator>Bando, Toshikazu</creator><creator>Sugiyama, Hiroshi</creator><general>Wiley Subscription Services, Inc</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>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>K9.</scope><orcidid>https://orcid.org/0000-0001-8923-5946</orcidid></search><sort><creationdate>20210205</creationdate><title>Evaluation of the DNA Alkylation Properties of a Chlorambucil‐Conjugated Cyclic Pyrrole‐Imidazole Polyamide</title><author>Hirose, Yuki ; Hashiya, Kaori ; Bando, Toshikazu ; Sugiyama, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4941-3969d38f99f71cc7d37e2b3e835d722606a0e67a7e69a609f88f40f4c51aac6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenine</topic><topic>Alkylates</topic><topic>Alkylation</topic><topic>Antifungal agents</topic><topic>Antitumor agents</topic><topic>Binding sites</topic><topic>Cancer</topic><topic>Capillary electrophoresis</topic><topic>Chemistry</topic><topic>Chlorambucil</topic><topic>Chlorambucil - chemistry</topic><topic>Conjugates</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA - chemistry</topic><topic>DNA alkylator</topic><topic>DNA recognition</topic><topic>drug delivery</topic><topic>Drugs</topic><topic>Electrophoresis</topic><topic>High-performance liquid chromatography</topic><topic>Imidazole</topic><topic>Imidazoles - chemistry</topic><topic>Liquid chromatography</topic><topic>Nucleotide sequence</topic><topic>Nylons - chemistry</topic><topic>Polyamide resins</topic><topic>Polyamides</topic><topic>Prostate cancer</topic><topic>Pyrroles - chemistry</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hirose, Yuki</creatorcontrib><creatorcontrib>Hashiya, Kaori</creatorcontrib><creatorcontrib>Bando, Toshikazu</creatorcontrib><creatorcontrib>Sugiyama, Hiroshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Chemistry : a European journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hirose, Yuki</au><au>Hashiya, Kaori</au><au>Bando, Toshikazu</au><au>Sugiyama, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of the DNA Alkylation Properties of a Chlorambucil‐Conjugated Cyclic Pyrrole‐Imidazole Polyamide</atitle><jtitle>Chemistry : a European journal</jtitle><addtitle>Chemistry</addtitle><date>2021-02-05</date><risdate>2021</risdate><volume>27</volume><issue>8</issue><spage>2782</spage><epage>2788</epage><pages>2782-2788</pages><issn>0947-6539</issn><eissn>1521-3765</eissn><abstract>Hairpin pyrrole‐imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP‐Chbs) can alkylate DNA in a sequence‐specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP‐Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP‐Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP‐Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP‐Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP‐Chbs could be novel DNA alkylating anticancer drugs.
Targeted alkylation: The DNA alkylation properties of a cyclic pyrrole‐imidazole polyamide that was conjugated with the DNA‐alkylator chlorambucil are reported. The conjugate shows good alkylation ability in vitro and anticancer effects against cancer cells.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>33145851</pmid><doi>10.1002/chem.202004421</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-8923-5946</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenine Alkylates Alkylation Antifungal agents Antitumor agents Binding sites Cancer Capillary electrophoresis Chemistry Chlorambucil Chlorambucil - chemistry Conjugates Cytotoxicity Deoxyribonucleic acid DNA DNA - chemistry DNA alkylator DNA recognition drug delivery Drugs Electrophoresis High-performance liquid chromatography Imidazole Imidazoles - chemistry Liquid chromatography Nucleotide sequence Nylons - chemistry Polyamide resins Polyamides Prostate cancer Pyrroles - chemistry Toxicity |
| title | Evaluation of the DNA Alkylation Properties of a Chlorambucil‐Conjugated Cyclic Pyrrole‐Imidazole Polyamide |
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