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

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• 作者：Girish Chandra ; Yang Won Moon ; Yoonji Lee ; Ji Yong Jang ; Jayoung Song ; Akshata Nayak ; Kawon Oh ; Varughese A. Mulamoottil ; Pramod K. Sahu ; Gyudong Kim ; Tong-Shin Chang ; Minsoo Noh ; Sang Kook Lee ; Sun Choi ; Lak Shin Jeong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：5108-5120
• 全文大小：545K
• ISSN：1520-4804

文摘

On the basis of the potent inhibitory activity of neplanocin A (1) against S-adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure鈥揳ctivity 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鈥?position with fluorine increased the inhibitory activity of the enzyme. The one-carbon homologation at the 5鈥?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鈥?fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC₅₀ = 0.24 渭M). It showed a potent anti-VSV activity (EC₅₀ = 0.43 渭M) and potent anticancer activity in all the human tumor cell lines tested.