| Reference | [1]. Bioorg Med Chem. 2016 Aug 15;24(16):3856-61. doi: 10.1016/j.bmc.2016.06.030. Epub 2016 Jun 18.<br />
Effects of 8-halo-7-deaza-2'-deoxyguanosine triphosphate on DNA synthesis by DNA polymerases and cell proliferation.<br />
Yin Y(1), Sasaki S(1), Taniguchi Y(2).<br />
Author information: (1)Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. (2)Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: [email protected].<br />
8-OxodG (8-oxo-2'-deoxyguanosine) is representative of nucleoside damage and shows a genotoxicity. To significantly reveal the contributions of 7-NH and C8-oxygen to the mutagenic effect of 8-oxodG by DNA polymerases, we evaluated the effects of the 8-halo-7-deaza-dG (8-halogenated 7-deaza-2'-deoxyguanosine) derivatives by DNA polymerases. 8-Halo-7-deaza-dGTPs were poorly incorporated by both KF(exo(-)) and human DNA polymerase β opposite dC or dA into the template DNA. Furthermore, it was found that KF(exo(-)) was very sensitive to the introduction of the C8-halogen, while polymerase β can accommodate the C8-halogen resulting in an efficient dCTP insertion opposite the 8-halo-7-deaza-dG in the template DNA. These results indicate that strong hydrogen bonding between 7-NH in the 8-oxo-G nucleobase and 1-N in the adenine at the active site of the DNA polymerase is required for the mutagenic effects. Whereas, I-deaza-dGTP shows an antiproliferative effect for the HeLa cells, suggesting that it could become a candidate as a new antitumor agent.<br />
DOI: 10.1016/j.bmc.2016.06.030 PMID: 27372838 [Indexed for MEDLINE]<br />
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[2]. Chembiochem. 2016 Apr 1;17(7):566-9. doi: 10.1002/cbic.201500589. Epub 2016 Feb 16.<br />
Inhibitory Effect of 8-Halogenated 7-Deaza-2'-deoxyguanosine Triphosphates on Human 8-Oxo-2'-deoxyguanosine Triphosphatase, hMTH1, Activities.<br />
Yin Y(1), Sasaki S(1), Taniguchi Y(2).<br />
Author information: (1)Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. (2)Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. [email protected].<br />
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.<br />
DOI: 10.1002/cbic.201500589 PMID: 26879218 [Indexed for MEDLINE]<br />
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[3]. DNA Seq. 1991;1(4):233-9. doi: 10.3109/10425179109020778.<br />
Improvements in the chain-termination method of DNA sequencing through the use of 7-deaza-2'-deoxyadenosine.<br />
Jensen MA(1), Zagursky RJ, Trainor GL, Cocuzza AJ, Lee A, Chen EY.<br />
Author information: (1)Central Research and Development Department, E.I. du Pont de Nemours & Company (Inc.), Wilmington, DE 19898.<br />
Significant improvements in the quality of DNA sequencing data have been shown when deoxyadenosine triphosphate (dATP) is replaced by 7-deaza-2'-deoxyadenosine triphosphate (c7dATP). The use of c7dATP in conjunction with 7-deaza-2'-deoxyguanosine triphosphate (c7dGTP) further decreases anomalies in electrophoretic mobility which are caused by compressions involving G and/or A residues. This effect is observed for both isotope-based and fluorescence-based sequencing approaches. Replacing dATP with c7dATP also results in a higher degree of uniformity in the frequency of chain termination reactions, when such terminations involve the incorporation of fluorescence-labeled dideoxynucleotides by T7 polymerase. These improvements in the gel-resolution and distribution of chain-terminated DNA products result in higher accuracy in both manual and automated base assignment.<br />
DOI: 10.3109/10425179109020778 PMID: 1806040 [Indexed for MEDLINE]<br />
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[4]. Biochemistry. 1996 Dec 10;35(49):15611-7. doi: 10.1021/bi961228v.<br />
Human telomerase inhibition by 7-deaza-2'-deoxypurine nucleoside triphosphates.<br />
Fletcher TM(1), Salazar M, Chen SF.<br />
Author information: (1)Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas 78245, USA.<br />
Telomeres play an important role in chromosome organization and stability. Human telomerase is a terminal transferase that adds TTAGGG units onto the telomere end. In general, telomerase activity is not detected in normal somatic cells but is present in immortalized cells. Consequently, telomerase might be a selective target for cancer chemotherapy. Using cell-free biochemical telomerase assay, we have found that 7-deaza-2'-deoxyguanosine-5'-triphosphate (7-deaza-dGTP) and 7-deaza-2'-deoxyadenosine-5'-triphosphate (7-deaza-dATP) were potent telomerase inhibitors. The concentrations of inhibitors in which 50% of the telomerase activity was inhibited (IC50 values) were 11 and 8 microM for 7-deaza-dGTP and 7-deaza-dATP, respectively. Additional studies show that both 7-deaza-dGTP and 7-deaza-dATP were also incorporated into telomeric DNA by telomerase. However, incorporation of 7-deaza-dATP or 7-deaza-dGTP results in a telomeric ladder that is prematurely shortened. No difference in the number or position of pause sites were observed when 7-deaza-dATP was compared to dATP as substrates. On the other hand, both a shift and an increase in pause sites was observed when dGTP was replaced by 7-deaza-dGTP. Incorporation of 7-deaza nucleotides by telomerase may be used as a tool for the study of telomerase mechanism and function. In addition, this may be a novel approach in the design of new telomerase inhibitors.<br />
DOI: 10.1021/bi961228v PMID: 8961922 [Indexed for MEDLINE]<br />
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[5]. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1187-92. doi: 10.1073/pnas.96.4.1187.<br />
Femtosecond dynamics of the DNA intercalator ethidium and electron transfer with mononucleotides in water.<br />
Fiebig T(1), Wan C, Kelley SO, Barton JK, Zewail AH.<br />
Author information: (1)Laboratory for Molecular Science, Arthur Amos Noyes Laboratory of Chemical Physics, California Institute of Technology, Pasadena, CA 91125, USA.<br />
Ethidium (E) is a powerful probe of DNA dynamics and DNA-mediated electron transfer (ET). Molecular dynamical processes, such as solvation and orientation, are important on the time scale of ET. Here, we report studies of the femtosecond and picosecond time-resolved dynamics of E, E with 2'deoxyguanosine triphosphate (GTP) in water, and E with 7-deaza-2'-deoxyguanosine triphosphate (ZTP) in water; E undergoes ET with ZTP but not GTP. These studies elucidate the critical role of relative orientational motions of the donor-acceptor complex on ET processes in solution. For ET from ZTP to E, such motions are in fact the rate-determining step. Our results indicate that these complexes reorient before ET. The time scale for the solvation of E in water is 1 ps, and the orientational relaxation time of E is 70 ps. The impact of orientational and solvation effects on ET between E and mononucleotides must be considered in the application of E as a probe of DNA ET.<br />
DOI: 10.1073/pnas.96.4.1187 PMCID: PMC15438 PMID: 9989999 [Indexed for MEDLINE]
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