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

被引:33
作者
Chandra, Girish [1 ,2 ]
Moon, Yang Won [3 ]
Lee, Yoonji [3 ]
Jang, Ji Yong [3 ]
Song, Jayoung [1 ]
Nayak, Akshata [1 ]
Oh, Kawon [1 ,3 ]
Mulamoottil, Varughese A. [3 ]
Sahu, Pramod K. [1 ]
Kim, Gyudong [1 ]
Chang, Tong-Shin [3 ]
Noh, Minsoo [1 ]
Lee, Sang Kook [1 ]
Choi, Sun [3 ]
Jeong, Lak Shin [1 ]
机构
[1] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea
[2] Cent Univ Bihar, Sch Chem & Phys Sci, Dept Chem, Gaya 823001, Bihar, India
[3] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Seoul 120750, South Korea
基金
新加坡国家研究基金会;
关键词
L-HOMOCYSTEINE HYDROLASE; STEREOSELECTIVE-SYNTHESIS; CARBOCYCLIC NUCLEOSIDES; BIOLOGICAL EVALUATION; MECHANISM; DESIGN; POTENT;
D O I
10.1021/acs.jmedchem.5b00553
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:5108 / 5120
页数:13
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