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ID: ALA3580643
Journal: J Med Chem
Title: Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities.
Authors: Chandra G, Moon YW, Lee Y, Jang JY, Song J, Nayak A, Oh K, Mulamoottil VA, Sahu PK, Kim G, Chang TS, Noh M, Lee SK, Choi S, Jeong LS.
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 μM). It showed a potent anti-VSV activity (EC50 = 0.43 μM) and potent anticancer activity in all the human tumor cell lines tested.
CiteXplore: 26010585