Structure-Activity Relationships of Neplanocin A Analogues as S -Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities
- 등재 SCIE, SCOPUS
- 발행기관 American Chemical Society
- 발행년도 2015
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000118239
- 본문언어 영어
- Published As http://dx.doi.org/10.1021/acs.jmedchem.5b00553
초록/요약
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 (IC<inf>50</inf> = 0.24 μM). It showed a potent anti-VSV activity (EC<inf>50</inf> = 0.43 μM) and potent anticancer activity in all the human tumor cell lines tested. © 2015 American Chemical Society.
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