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Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities
- Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities
- Chandra, Girish; Moon, Yang Won; Lee, Yoonji; Jang, Ji Yong; Song, Jayoung; Nayak, Akshata; Oh, Kawon; Mulamoottil, Varughese A.; Sahu, Pramod K.; Kim, Gyudong; Chang, Tong-Shin; Noh, Minsoo; Lee, Sang Kook; Choi, Sun; Jeong, Lak Shin
- Ewha Authors
- 창동신; 최선
- SCOPUS Author ID
- 창동신; 최선
- Issue Date
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- 0022-2623; 1520-4804
- vol. 58, no. 12, pp. 5108 - 5120
- AMER CHEMICAL SOC
- SCI; SCIE; SCOPUS
- 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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