A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase
Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as te...
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| Veröffentlicht in: | Organic & biomolecular chemistry 2024-04, Vol.22 (14), p.2749-2753 |
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| container_issue | 14 |
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| container_title | Organic & biomolecular chemistry |
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| creator | Seylan Ayan Rotaru, Adrian M Kaye, Esther G Juneau, Gabrielle Das, Sunit Wilds, Christopher J Beharry, Andrew A |
| description | Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. Overall, our chloromethyl triazole-based fluorescence MGMT probe is a promising tool for measuring MGMT activity to predict temozolomide resistance. |
| doi_str_mv | 10.1039/d4ob00120f |
| format | Article |
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O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. 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O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. Overall, our chloromethyl triazole-based fluorescence MGMT probe is a promising tool for measuring MGMT activity to predict temozolomide resistance.</description><subject>Alkylating agents</subject><subject>Alkylation</subject><subject>Anticancer properties</subject><subject>Antineoplastic drugs</subject><subject>Chemical sensors</subject><subject>Chemoreceptors</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methyltransferase</subject><subject>DNA probes</subject><subject>Drug discovery</subject><subject>Drug resistance</subject><subject>Enzymatic activity</subject><subject>Enzyme activity</subject><subject>Fluorescence</subject><subject>Fluorescent indicators</subject><subject>Inhibitors</subject><subject>Methylguanine</subject><subject>O6-methylguanine-DNA methyltransferase</subject><subject>Substrate inhibition</subject><subject>Temozolomide</subject><subject>Triazoles</subject><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpdzj1PwzAQBmALgUQpLPyCSCwsAduXD3usyqdU0aUTS-Q4Z5rKsYudDPDrsRTEwHC606tHp5eQa0bvGAV53xW-pZRxak7IghV1ndMS5Onfzek5uYjxkIysq2JB3leZ3lsf_IDj_svmY-jVt7eYGTv5gFGjG5PAwUd00YfMpNlW-cw_JuV6h9nD2yqbkzEoFw0GFfGSnBllI1797iXZPT3u1i_5Zvv8ul5t8iMrqjHHrqy50GBKYFqLroQOeNWWbcsMQKlAUCmFFppjUqoTIGTXFjVDCoJrWJLb-e0x-M8J49gMfaptrXLop9hwWQnJQQie6M0_evBTcKlcAxQYE7ymBfwAsxpiqQ</recordid><startdate>20240403</startdate><enddate>20240403</enddate><creator>Seylan Ayan</creator><creator>Rotaru, Adrian M</creator><creator>Kaye, Esther G</creator><creator>Juneau, Gabrielle</creator><creator>Das, Sunit</creator><creator>Wilds, Christopher J</creator><creator>Beharry, Andrew A</creator><general>Royal Society of Chemistry</general><scope>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20240403</creationdate><title>A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase</title><author>Seylan Ayan ; Rotaru, Adrian M ; Kaye, Esther G ; Juneau, Gabrielle ; Das, Sunit ; Wilds, Christopher J ; Beharry, Andrew A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p146t-ed5728c3f531cc8d53d326b5bb1f335a380998c8c2e8c3ad8389db471e0382c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alkylating agents</topic><topic>Alkylation</topic><topic>Anticancer properties</topic><topic>Antineoplastic drugs</topic><topic>Chemical sensors</topic><topic>Chemoreceptors</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methyltransferase</topic><topic>DNA probes</topic><topic>Drug discovery</topic><topic>Drug resistance</topic><topic>Enzymatic activity</topic><topic>Enzyme activity</topic><topic>Fluorescence</topic><topic>Fluorescent indicators</topic><topic>Inhibitors</topic><topic>Methylguanine</topic><topic>O6-methylguanine-DNA methyltransferase</topic><topic>Substrate inhibition</topic><topic>Temozolomide</topic><topic>Triazoles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seylan Ayan</creatorcontrib><creatorcontrib>Rotaru, Adrian M</creatorcontrib><creatorcontrib>Kaye, Esther G</creatorcontrib><creatorcontrib>Juneau, Gabrielle</creatorcontrib><creatorcontrib>Das, Sunit</creatorcontrib><creatorcontrib>Wilds, Christopher J</creatorcontrib><creatorcontrib>Beharry, Andrew A</creatorcontrib><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seylan Ayan</au><au>Rotaru, Adrian M</au><au>Kaye, Esther G</au><au>Juneau, Gabrielle</au><au>Das, Sunit</au><au>Wilds, Christopher J</au><au>Beharry, Andrew A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase</atitle><jtitle>Organic & biomolecular chemistry</jtitle><date>2024-04-03</date><risdate>2024</risdate><volume>22</volume><issue>14</issue><spage>2749</spage><epage>2753</epage><pages>2749-2753</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><abstract>Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. Overall, our chloromethyl triazole-based fluorescence MGMT probe is a promising tool for measuring MGMT activity to predict temozolomide resistance.</abstract><cop>Cambridge</cop><pub>Royal Society of Chemistry</pub><doi>10.1039/d4ob00120f</doi><tpages>5</tpages></addata></record> |
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| ispartof | Organic & biomolecular chemistry, 2024-04, Vol.22 (14), p.2749-2753 |
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| source | Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| subjects | Alkylating agents Alkylation Anticancer properties Antineoplastic drugs Chemical sensors Chemoreceptors Deoxyribonucleic acid DNA DNA methyltransferase DNA probes Drug discovery Drug resistance Enzymatic activity Enzyme activity Fluorescence Fluorescent indicators Inhibitors Methylguanine O6-methylguanine-DNA methyltransferase Substrate inhibition Temozolomide Triazoles |
| title | A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase |
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