Insight into the deamination mechanism of 6-cyclopropylamino guanosine analogs for anti-HIV drug design |
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Authors: | Xin-Meng Fan Xian-Tao Yang Yu-Jia Guo Ren-Min Wu De-Lin Pan Zhu Guan Xiao-Mei Ling Li-He Zhang Zhen-Jun Yang |
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Institution: | State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China |
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Abstract: | 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. |
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Keywords: | Deamination 6-Cyclopropylamino guanosine Mouse liver homogenate Adenosine deaminase Anti-HIV drug design |
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