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

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

Research output: Contribution to journalArticle

16 Scopus citations

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 languageEnglish (US)
Pages (from-to)5108-5120
Number of pages13
JournalJournal of Medicinal Chemistry
Volume58
Issue number12
DOIs
StatePublished - Jun 25 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Chandra, G., Moon, Y. W., Lee, Y., Jang, J. Y., Song, J., Nayak, A., Oh, K., Mulamoottil, V. A., Sahu, P. K., Kim, G., Chang, T. S., Noh, M., Lee, S. K., Choi, S., & Jeong, L. S. (2015). Structure-Activity Relationships of Neplanocin A Analogues as S -Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities. Journal of Medicinal Chemistry, 58(12), 5108-5120. https://doi.org/10.1021/acs.jmedchem.5b00553