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

  • J Med Chem. 2015 Jun 25;58(12):5108-20. doi: 10.1021/acs.jmedchem.5b00553.
Girish Chandra  1  2 ,  Yang Won Moon  3 ,  Yoonji Lee  3 ,  Ji Yong Jang  3 ,  Jayoung Song  1 ,  Akshata Nayak  1 ,  Kawon Oh  1  3 ,  Varughese A Mulamoottil  3 ,  Pramod K Sahu  1 ,  Gyudong Kim  1 ,  Tong-Shin Chang  3 ,  Minsoo Noh  1 ,  Sang Kook Lee  1 ,  Sun Choi  3 ,  Lak Shin Jeong  1
Affiliations
  • 1. †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
  • 2. ‡Department of Chemistry, School of Chemical and Physical Sciences, Central University of Bihar, Gaya, Bihar, 823001, India.
  • 3. §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
PMID: 26010585 DOI: 10.1021/acs.jmedchem.5b00553
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.