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Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities

Title
Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities
Authors
Chandra, GirishMoon, Yang WonLee, YoonjiJang, Ji YongSong, JayoungNayak, AkshataOh, KawonMulamoottil, Varughese A.Sahu, Pramod K.Kim, GyudongChang, Tong-ShinNoh, MinsooLee, Sang KookChoi, SunJeong, Lak Shin
Ewha Authors
창동신최선
SCOPUS Author ID
창동신scopus; 최선scopus
Issue Date
2015
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link1520-4804JCR Link
Citation
vol. 58, no. 12, pp. 5108 - 5120
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
On the basis of the potent inhibitory activity of neplanocin A (1) against S-adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure-activity relationships by modifying the adenine and carbasugar moiety of 1 to find the pharmacophore in the active site of the enzyme. The introduction of 7-deazaadenine instead of adenine eliminated the inhibitory activity against the AdoHcy hydrolase, while 3-deazaadenine maintained the inhibitory activity of the enzyme, indicating that N-7 is essential for its role as a hydrogen bonding acceptor. The substitution of hydrogen at the 6'-position with fluorine increased the inhibitory activity Of the enzyme. The one-carbon homologation at the 5'-position generally decreased the inhibitory activity of the enzyme, indicating that steric repulsion exists. A molecular docking study also supported these experimental data. In this study, 6'-fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC50 = 0.24 mu M). It showed a potent anti-VSV activity (EC50 = 0.43 mu M) and potent anticancer activity in all the human tumor cell lines tested.
DOI
10.1021/acs.jmedchem.5b00553
Appears in Collections:
약학대학 > 약학과 > Journal papers
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