title: Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities.
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.
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.|‡Department of Chemistry, School of Chemical and Physical Sciences, Central University of Bihar, Gaya, Bihar, 823001, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Chandra
authors.affiliation: §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Yang Won
authors.initials: YW
authors.lastname: Moon
authors.affiliation: §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.affiliation: §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Ji Yong
authors.initials: JY
authors.lastname: Jang
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Song
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Akshata
authors.initials: A
authors.lastname: Nayak
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.|§College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Kawon
authors.initials: K
authors.lastname: Oh
authors.affiliation: §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Varughese A
authors.initials: VA
authors.lastname: Mulamoottil
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Sahu
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Gyudong
authors.initials: G
authors.lastname: Kim
authors.affiliation: §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Tong-Shin
authors.initials: TS
authors.lastname: Chang
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Noh
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.affiliation: §College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: †Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014777:Virus Diseases / Q000188:drug therapy; D014780:Viruses / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C043837:7-deazaadenine; C055133:3-deazaadenine; C031096:neplanocin A; D043383:Adenosylhomocysteinase; D000225:Adenine; D000241:Adenosine