Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 12, Pages 5108-5120Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00553
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Funding
- Midcareer Research Program through Ministry of Science, ICT & Future Planning (MSIP) [370C-20130120]
- National Leading Research Lab (NLRL) program through Ministry of Science, ICT & Future Planning (MSIP) [2011-0028885]
- National Research Foundation (NRF) of Korea
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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.
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