Inhibitory Effect of 8-Halogenated 7-Deaza-2′-deoxyguanosine Triphosphates on Human 8-Oxo-2′-deoxyguanosine Triphosphatase, hMTH1, Activities
hMTH1 (8‐oxo‐2′‐deoxyguanine triphosphatase) hydrolyzes oxidized nucleoside triphosphates; its presence is non‐essential for survival of normal cells but is required for survival of cancer cells. In this study, 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine triphosphate (8‐halogenated‐7‐deazadGTP) derivati...
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| Veröffentlicht in: | Chembiochem : a European journal of chemical biology 2016-04, Vol.17 (7), p.566-569 |
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| creator | Yin, Yizhen Sasaki, Shigeki Taniguchi, Yosuke |
| description | hMTH1 (8‐oxo‐2′‐deoxyguanine triphosphatase) hydrolyzes oxidized nucleoside triphosphates; its presence is non‐essential for survival of normal cells but is required for survival of cancer cells. In this study, 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine triphosphate (8‐halogenated‐7‐deazadGTP) derivatives were synthesized. Interestingly, these triphosphates were poor substrates for hMTH1, but exhibited strong competitive inhibition against hMTH1 at nanomolar levels. This inhibitory effect is attributed to slower rate of hydrolysis, possibly arising from enzyme structural changes, specifically different stacking interactions with 8‐halogenated‐7‐deazadGTP. This is the first example of using nucleotide derivatives to inhibit hMTH1, thus demonstrating their potential as antitumor agents.
New inhibitors: We synthesized triphosphate 8‐halogenated‐7‐deazadG derivatives and showed their inhibitory effects on the human 8‐oxo‐2′‐deoxyguanosine triphosphatase, hMTH1. These triphosphates are poor substrates for hMTH1, but exhibit strong competitive inhibition against hMTH1 at nanomolar levels. Therefore, they are candidates as novel antitumor agents. |
| doi_str_mv | 10.1002/cbic.201500589 |
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New inhibitors: We synthesized triphosphate 8‐halogenated‐7‐deazadG derivatives and showed their inhibitory effects on the human 8‐oxo‐2′‐deoxyguanosine triphosphatase, hMTH1. These triphosphates are poor substrates for hMTH1, but exhibit strong competitive inhibition against hMTH1 at nanomolar levels. Therefore, they are candidates as novel antitumor agents.</description><identifier>ISSN: 1439-4227</identifier><identifier>EISSN: 1439-7633</identifier><identifier>DOI: 10.1002/cbic.201500589</identifier><identifier>PMID: 26879218</identifier><language>eng</language><publisher>Germany: Blackwell Publishing Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; cancer ; Chromatography, High Pressure Liquid ; Deoxyguanine Nucleotides - chemical synthesis ; Deoxyguanine Nucleotides - chemistry ; Deoxyguanine Nucleotides - pharmacology ; DNA Repair Enzymes - antagonists & inhibitors ; DNA Repair Enzymes - metabolism ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; halogenated deazadeoxyguanosine triphosphate ; Halogens - chemical synthesis ; Halogens - chemistry ; hMTH1 ; Humans ; inhibitors ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Molecular Structure ; oxo-dGTP ; Phosphoric Monoester Hydrolases - antagonists & inhibitors ; Phosphoric Monoester Hydrolases - metabolism</subject><ispartof>Chembiochem : a European journal of chemical biology, 2016-04, Vol.17 (7), p.566-569</ispartof><rights>2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5149-6b6856a758a20824ee334436cd851654ed03e93772e7c4abb7fcdeecded042d43</citedby><cites>FETCH-LOGICAL-c5149-6b6856a758a20824ee334436cd851654ed03e93772e7c4abb7fcdeecded042d43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcbic.201500589$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcbic.201500589$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26879218$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yin, Yizhen</creatorcontrib><creatorcontrib>Sasaki, Shigeki</creatorcontrib><creatorcontrib>Taniguchi, Yosuke</creatorcontrib><title>Inhibitory Effect of 8-Halogenated 7-Deaza-2′-deoxyguanosine Triphosphates on Human 8-Oxo-2′-deoxyguanosine Triphosphatase, hMTH1, Activities</title><title>Chembiochem : a European journal of chemical biology</title><addtitle>ChemBioChem</addtitle><description>hMTH1 (8‐oxo‐2′‐deoxyguanine triphosphatase) hydrolyzes oxidized nucleoside triphosphates; its presence is non‐essential for survival of normal cells but is required for survival of cancer cells. In this study, 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine triphosphate (8‐halogenated‐7‐deazadGTP) derivatives were synthesized. Interestingly, these triphosphates were poor substrates for hMTH1, but exhibited strong competitive inhibition against hMTH1 at nanomolar levels. This inhibitory effect is attributed to slower rate of hydrolysis, possibly arising from enzyme structural changes, specifically different stacking interactions with 8‐halogenated‐7‐deazadGTP. This is the first example of using nucleotide derivatives to inhibit hMTH1, thus demonstrating their potential as antitumor agents.
New inhibitors: We synthesized triphosphate 8‐halogenated‐7‐deazadG derivatives and showed their inhibitory effects on the human 8‐oxo‐2′‐deoxyguanosine triphosphatase, hMTH1. These triphosphates are poor substrates for hMTH1, but exhibit strong competitive inhibition against hMTH1 at nanomolar levels. Therefore, they are candidates as novel antitumor agents.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>cancer</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Deoxyguanine Nucleotides - chemical synthesis</subject><subject>Deoxyguanine Nucleotides - chemistry</subject><subject>Deoxyguanine Nucleotides - pharmacology</subject><subject>DNA Repair Enzymes - antagonists & inhibitors</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>halogenated deazadeoxyguanosine triphosphate</subject><subject>Halogens - chemical synthesis</subject><subject>Halogens - chemistry</subject><subject>hMTH1</subject><subject>Humans</subject><subject>inhibitors</subject><subject>Inhibitory Concentration 50</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Structure</subject><subject>oxo-dGTP</subject><subject>Phosphoric Monoester Hydrolases - antagonists & inhibitors</subject><subject>Phosphoric Monoester Hydrolases - metabolism</subject><issn>1439-4227</issn><issn>1439-7633</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctu00AUhi1ERUthyxKNxIZFHeY-9rJ1L4la2k2A5Wg8Pm6mOJ4wY9OkK16BV-GReJI6SogqNl0cnbP4_k9H-pPkHcEjgjH9ZEtnRxQTgbHI8hfJAeEsT5Vk7OX25pSq_eR1jHcY41wy8irZpzJTOSXZQfJ70s5c6TofVuisrsF2yNcoS8em8bfQmg4qpNJTMA8mpX9__Ukr8MvVbW9aH10LaBrcYubjYjaQEfkWjfu5aQfBzdI_FzARjtDs83RMjtCx7dxP1zmIb5K92jQR3m73YfLl_GxajNOrm4tJcXyVWkF4nspSZkIaJTJDcUY5AGOcM2mrTBApOFSYQc6UoqAsN2WpalsBDFNhTivODpOPG-8i-B89xE7PXbTQNKYF30dNlMo4xoyKAf3wH3rn-9AO360ppSQRORmo0YaywccYoNaL4OYmrDTBel2WXpeld2UNgfdbbV_Oodrh_9oZgHwD3LsGVs_odHEyKZ7K003WxQ6Wu6wJ37VUTAn97fpCi3N2Wlx-ZfqSPQKXB7H2</recordid><startdate>20160401</startdate><enddate>20160401</enddate><creator>Yin, Yizhen</creator><creator>Sasaki, Shigeki</creator><creator>Taniguchi, Yosuke</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QL</scope><scope>7QO</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20160401</creationdate><title>Inhibitory Effect of 8-Halogenated 7-Deaza-2′-deoxyguanosine Triphosphates on Human 8-Oxo-2′-deoxyguanosine Triphosphatase, hMTH1, Activities</title><author>Yin, Yizhen ; Sasaki, Shigeki ; Taniguchi, Yosuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5149-6b6856a758a20824ee334436cd851654ed03e93772e7c4abb7fcdeecded042d43</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>cancer</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Deoxyguanine Nucleotides - chemical synthesis</topic><topic>Deoxyguanine Nucleotides - chemistry</topic><topic>Deoxyguanine Nucleotides - pharmacology</topic><topic>DNA Repair Enzymes - antagonists & inhibitors</topic><topic>DNA Repair Enzymes - metabolism</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>halogenated deazadeoxyguanosine triphosphate</topic><topic>Halogens - chemical synthesis</topic><topic>Halogens - chemistry</topic><topic>hMTH1</topic><topic>Humans</topic><topic>inhibitors</topic><topic>Inhibitory Concentration 50</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular Structure</topic><topic>oxo-dGTP</topic><topic>Phosphoric Monoester Hydrolases - antagonists & inhibitors</topic><topic>Phosphoric Monoester Hydrolases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yin, Yizhen</creatorcontrib><creatorcontrib>Sasaki, Shigeki</creatorcontrib><creatorcontrib>Taniguchi, Yosuke</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chembiochem : a European journal of chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yin, Yizhen</au><au>Sasaki, Shigeki</au><au>Taniguchi, Yosuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitory Effect of 8-Halogenated 7-Deaza-2′-deoxyguanosine Triphosphates on Human 8-Oxo-2′-deoxyguanosine Triphosphatase, hMTH1, Activities</atitle><jtitle>Chembiochem : a European journal of chemical biology</jtitle><addtitle>ChemBioChem</addtitle><date>2016-04-01</date><risdate>2016</risdate><volume>17</volume><issue>7</issue><spage>566</spage><epage>569</epage><pages>566-569</pages><issn>1439-4227</issn><eissn>1439-7633</eissn><abstract>hMTH1 (8‐oxo‐2′‐deoxyguanine triphosphatase) hydrolyzes oxidized nucleoside triphosphates; its presence is non‐essential for survival of normal cells but is required for survival of cancer cells. In this study, 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine triphosphate (8‐halogenated‐7‐deazadGTP) derivatives were synthesized. Interestingly, these triphosphates were poor substrates for hMTH1, but exhibited strong competitive inhibition against hMTH1 at nanomolar levels. This inhibitory effect is attributed to slower rate of hydrolysis, possibly arising from enzyme structural changes, specifically different stacking interactions with 8‐halogenated‐7‐deazadGTP. This is the first example of using nucleotide derivatives to inhibit hMTH1, thus demonstrating their potential as antitumor agents.
New inhibitors: We synthesized triphosphate 8‐halogenated‐7‐deazadG derivatives and showed their inhibitory effects on the human 8‐oxo‐2′‐deoxyguanosine triphosphatase, hMTH1. These triphosphates are poor substrates for hMTH1, but exhibit strong competitive inhibition against hMTH1 at nanomolar levels. Therefore, they are candidates as novel antitumor agents.</abstract><cop>Germany</cop><pub>Blackwell Publishing Ltd</pub><pmid>26879218</pmid><doi>10.1002/cbic.201500589</doi><tpages>4</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology cancer Chromatography, High Pressure Liquid Deoxyguanine Nucleotides - chemical synthesis Deoxyguanine Nucleotides - chemistry Deoxyguanine Nucleotides - pharmacology DNA Repair Enzymes - antagonists & inhibitors DNA Repair Enzymes - metabolism Enzyme Activation - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology halogenated deazadeoxyguanosine triphosphate Halogens - chemical synthesis Halogens - chemistry hMTH1 Humans inhibitors Inhibitory Concentration 50 Molecular Dynamics Simulation Molecular Structure oxo-dGTP Phosphoric Monoester Hydrolases - antagonists & inhibitors Phosphoric Monoester Hydrolases - metabolism |
| title | Inhibitory Effect of 8-Halogenated 7-Deaza-2′-deoxyguanosine Triphosphates on Human 8-Oxo-2′-deoxyguanosine Triphosphatase, hMTH1, Activities |
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