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.
Original language | English |
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Pages (from-to) | 5108-5120 |
Number of pages | 13 |
Journal | Journal of Medicinal Chemistry |
Volume | 58 |
Issue number | 12 |
DOIs | |
State | Published - 25 Jun 2015 |
Bibliographical note
Publisher Copyright:© 2015 American Chemical Society.