Citation: Fan Xin-Meng, Yang Xian-Tao, Guo Yu-Jia, Wu Ren-Min, Pan De-Lin, Guan Zhu, Ling Xiao-Mei, Zhang Li-He, Yang Zhen-Jun. Insight into the deamination mechanism of 6-cyclopropylamino guanosine analogs for anti-HIV drug design[J]. Chinese Chemical Letters, ;2016, 27(12): 1759-1762. doi: 10.1016/j.cclet.2016.05.021 shu

Insight into the deamination mechanism of 6-cyclopropylamino guanosine analogs for anti-HIV drug design

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China

Corresponding author: Guan Zhu, guanzhu_gz@bjmu.edu.cn Yang Zhen-Jun, yangzj@bjmu.edu.cn
Received Date: 22 February 2016
Revised Date: 11 April 2016
Accepted Date: 22 April 2016
Available Online: 26 December 2016

Figures(5)

Deamination is a crucial step in the transformation of 6-cyclopropylamino guanosine prodrug to its active form. A convenient method using capillary electrophoresis (CE) without sample labeling was developed to analyze the deamination of a series of D-/L-6-cyclopropylamino guanosine analogs by mouse liver homogenate, mouse liver microsome, and adenosine deaminase (ADA). A two-step process involving a 6-amino guanosine intermediate formed by oxidative N-dealkylation was demonstrated in the metabolism of 6-cyclopropylamino guanosine to 6-hydroxy guanosine. The results indicated that the transformation rates of different prodrugs to the active form varied greatly, which were closely correlated with the configuration of nucleosides and the structure of glycosyl groups. Most importantly, D-form analogs were metabolized much faster than their L-counterparts, thus clearly pointed out that compared to guanine, modification of glycosyl part might be a better choice for the development of L-guanosine analogs for the treatment of HIV.
- Deamination,
- 6-Cyclopropylamino guanosine,
- Mouse liver homogenate,
- Adenosine deaminase,
- Anti-HIV drug design
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