TY - JOUR
T1 - Inhibitory Effect of 8-Halogenated 7-Deaza-2′-deoxyguanosine Triphosphates on Human 8-Oxo-2′-deoxyguanosine Triphosphatase, hMTH1, Activities
AU - Yin, Yizhen
AU - Sasaki, Shigeki
AU - Taniguchi, Yosuke
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Young Scientific (A) (Grant Number 24689006 for Y.T.) and Challenging Exploratory Research [grant number 24659047 for Y.T.] from the Japan Society for the Promotion of Science. Y.Y. was supported by the China Scholarship Council [grant number 2011622054]. This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Prof.Dr. Yusaku Nakabeppu (Kyushu University) for providing hMTH1 enzyme.
Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
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U2 - 10.1002/cbic.201500589
DO - 10.1002/cbic.201500589
M3 - Article
C2 - 26879218
AN - SCOPUS:84959162532
SN - 1439-4227
VL - 17
SP - 566
EP - 569
JO - ChemBioChem
JF - ChemBioChem
IS - 7
ER -
