Polar, functionalized guanine- O6 derivatives resistant to repair by O6 -alkylguanine–DNA alkyltransferase: implications for the design of DNA-modifying drugs
The protein O6 -alkylguanine–DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel O6-substituted guanine analogues...
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| Veröffentlicht in: | European journal of medicinal chemistry 2006-03, Vol.41 (3), p.330-339 |
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| container_issue | 3 |
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| container_title | European journal of medicinal chemistry |
| container_volume | 41 |
| creator | Pletsas, Dimitrios Wheelhouse, Richard T. Pletsa, Vassiliki Nicolaou, Anna Jenkins, Terence C. Bibby, Michael C. Kyrtopoulos, Soterios A. |
| description | The protein
O6
-alkylguanine–DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel
O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing
O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than
O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance. |
| doi_str_mv | 10.1016/j.ejmech.2005.11.007 |
| format | Article |
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O6
-alkylguanine–DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel
O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing
O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than
O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2005.11.007</identifier><identifier>PMID: 16458393</identifier><identifier>CODEN: EJMCA5</identifier><language>eng</language><publisher>Oxford: Elsevier Masson SAS</publisher><subject>Biological and medical sciences ; Crystallography, X-Ray ; DNA - chemistry ; DNA - drug effects ; DNA repair ; DNA Repair Enzymes - chemistry ; Drug Design ; Guanine - analogs & derivatives ; Guanine - chemistry ; Guanine - pharmacology ; Humans ; Medical sciences ; Miscellaneous ; Models, Biological ; Molecular Structure ; Mutation ; O-Methylguanine-DNA Methyltransferase - genetics ; O-Methylguanine-DNA Methyltransferase - metabolism ; O6 -alkylguanine–DNA alkyltransferase ; Pharmacology. Drug treatments ; Purine ; Purines - chemistry ; Purines - pharmacology ; Substrate Specificity</subject><ispartof>European journal of medicinal chemistry, 2006-03, Vol.41 (3), p.330-339</ispartof><rights>2006 Elsevier SAS</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-a1add3055332d0ebb14a4c5434c7258a6304e4478bca6b1966513511e3afd1e53</citedby><cites>FETCH-LOGICAL-c390t-a1add3055332d0ebb14a4c5434c7258a6304e4478bca6b1966513511e3afd1e53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523405003181$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17696099$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16458393$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pletsas, Dimitrios</creatorcontrib><creatorcontrib>Wheelhouse, Richard T.</creatorcontrib><creatorcontrib>Pletsa, Vassiliki</creatorcontrib><creatorcontrib>Nicolaou, Anna</creatorcontrib><creatorcontrib>Jenkins, Terence C.</creatorcontrib><creatorcontrib>Bibby, Michael C.</creatorcontrib><creatorcontrib>Kyrtopoulos, Soterios A.</creatorcontrib><title>Polar, functionalized guanine- O6 derivatives resistant to repair by O6 -alkylguanine–DNA alkyltransferase: implications for the design of DNA-modifying drugs</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>The protein
O6
-alkylguanine–DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel
O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing
O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than
O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance.</description><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>DNA - chemistry</subject><subject>DNA - drug effects</subject><subject>DNA repair</subject><subject>DNA Repair Enzymes - chemistry</subject><subject>Drug Design</subject><subject>Guanine - analogs & derivatives</subject><subject>Guanine - chemistry</subject><subject>Guanine - pharmacology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Biological</subject><subject>Molecular Structure</subject><subject>Mutation</subject><subject>O-Methylguanine-DNA Methyltransferase - genetics</subject><subject>O-Methylguanine-DNA Methyltransferase - metabolism</subject><subject>O6 -alkylguanine–DNA alkyltransferase</subject><subject>Pharmacology. Drug treatments</subject><subject>Purine</subject><subject>Purines - chemistry</subject><subject>Purines - pharmacology</subject><subject>Substrate Specificity</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUuO1DAQhiMEYpqBGyDkDaxIsONHEhZIo-EpjRgWsLYqdqXHTRL32ElLzYo7cIHsuEeOwklI0y3NjlVJpe-vKtWXJE8ZzRhl6tUmw02H5ibLKZUZYxmlxb1kxQpVpjyX4n6yonnOU5lzcZY8inFDF1BR-jA5Y0rIkld8lfz-4lsIL0kz9mZwvofW_UBL1iP0rseUXKt5shjcDga3w0gCRhcH6Acy-HkKuAUXSL2fp4UkKbTf9-0p--fnr7efL8i_1hCgjw0GiPiauG7bOgOHbZE0PszTcIOHLdGte-KbeVpyaeeta_auXxMbxnV8nDxooI345FTPk2_v3329_JheXX_4dHlxlRpe0SEFBtZyKiXnuaVY10yAMFJwYYpclqA4FShEUdYGVM0qpSTjkjHk0FiGkp8nL45zt8HfjhgH3blosG2hRz9GrYqyoDktF1AcQRN8jAEbvQ2ug7DXjOqDIL3RR0H6IEgzphdBS-zZaf5Yd2jvQicjC_D8BEA00DbL54yLd1yhKkWrauHeHDlcvrFzGHQ0DnuD1gU0g7be_f-SvzieuLQ</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Pletsas, Dimitrios</creator><creator>Wheelhouse, Richard T.</creator><creator>Pletsa, Vassiliki</creator><creator>Nicolaou, Anna</creator><creator>Jenkins, Terence C.</creator><creator>Bibby, Michael C.</creator><creator>Kyrtopoulos, Soterios A.</creator><general>Elsevier Masson SAS</general><general>Elsevier</general><scope>IQODW</scope><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>20060301</creationdate><title>Polar, functionalized guanine- O6 derivatives resistant to repair by O6 -alkylguanine–DNA alkyltransferase: implications for the design of DNA-modifying drugs</title><author>Pletsas, Dimitrios ; Wheelhouse, Richard T. ; Pletsa, Vassiliki ; Nicolaou, Anna ; Jenkins, Terence C. ; Bibby, Michael C. ; Kyrtopoulos, Soterios A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-a1add3055332d0ebb14a4c5434c7258a6304e4478bca6b1966513511e3afd1e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>DNA - chemistry</topic><topic>DNA - drug effects</topic><topic>DNA repair</topic><topic>DNA Repair Enzymes - chemistry</topic><topic>Drug Design</topic><topic>Guanine - analogs & derivatives</topic><topic>Guanine - chemistry</topic><topic>Guanine - pharmacology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Models, Biological</topic><topic>Molecular Structure</topic><topic>Mutation</topic><topic>O-Methylguanine-DNA Methyltransferase - genetics</topic><topic>O-Methylguanine-DNA Methyltransferase - metabolism</topic><topic>O6 -alkylguanine–DNA alkyltransferase</topic><topic>Pharmacology. Drug treatments</topic><topic>Purine</topic><topic>Purines - chemistry</topic><topic>Purines - pharmacology</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pletsas, Dimitrios</creatorcontrib><creatorcontrib>Wheelhouse, Richard T.</creatorcontrib><creatorcontrib>Pletsa, Vassiliki</creatorcontrib><creatorcontrib>Nicolaou, Anna</creatorcontrib><creatorcontrib>Jenkins, Terence C.</creatorcontrib><creatorcontrib>Bibby, Michael C.</creatorcontrib><creatorcontrib>Kyrtopoulos, Soterios A.</creatorcontrib><collection>Pascal-Francis</collection><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>Pletsas, Dimitrios</au><au>Wheelhouse, Richard T.</au><au>Pletsa, Vassiliki</au><au>Nicolaou, Anna</au><au>Jenkins, Terence C.</au><au>Bibby, Michael C.</au><au>Kyrtopoulos, Soterios A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Polar, functionalized guanine- O6 derivatives resistant to repair by O6 -alkylguanine–DNA alkyltransferase: implications for the design of DNA-modifying drugs</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>41</volume><issue>3</issue><spage>330</spage><epage>339</epage><pages>330-339</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><coden>EJMCA5</coden><abstract>The protein
O6
-alkylguanine–DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel
O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing
O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than
O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance.</abstract><cop>Oxford</cop><pub>Elsevier Masson SAS</pub><pmid>16458393</pmid><doi>10.1016/j.ejmech.2005.11.007</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0223-5234 |
| ispartof | European journal of medicinal chemistry, 2006-03, Vol.41 (3), p.330-339 |
| issn | 0223-5234 1768-3254 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Biological and medical sciences Crystallography, X-Ray DNA - chemistry DNA - drug effects DNA repair DNA Repair Enzymes - chemistry Drug Design Guanine - analogs & derivatives Guanine - chemistry Guanine - pharmacology Humans Medical sciences Miscellaneous Models, Biological Molecular Structure Mutation O-Methylguanine-DNA Methyltransferase - genetics O-Methylguanine-DNA Methyltransferase - metabolism O6 -alkylguanine–DNA alkyltransferase Pharmacology. Drug treatments Purine Purines - chemistry Purines - pharmacology Substrate Specificity |
| title | Polar, functionalized guanine- O6 derivatives resistant to repair by O6 -alkylguanine–DNA alkyltransferase: implications for the design of DNA-modifying drugs |
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