title: Inhibitory Effect of 8-Halogenated 7-Deaza-2'-deoxyguanosine Triphosphates on Human 8-Oxo-2'-deoxyguanosine Triphosphatase, hMTH1, Activities.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. taniguch@phar.kyushu-u.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Taniguchi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006219:Halogens / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D003848:Deoxyguanine Nucleotides; D004791:Enzyme Inhibitors; D006219:Halogens; C065361:2'-deoxy-7-deazaguanosine triphosphate; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes
keywords: cancer; hMTH1; halogenated deazadeoxyguanosine triphosphate; inhibitors; oxo-dGTP