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Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors
Li, Chao1; Ma, Chunying1; Zhang, Jin1; Qian, Ning1; Ding, Jingjing1; Qiao, Renzhong1,2; Zhao, Yufen3
关键词Nucleoside Analogue Anti-hiv Antiretrovirals Distamycin Protide
刊名ANTIVIRAL RESEARCH
2014-02-01
DOI10.1016/j.antiviral.2013.12.002
102页:54-60
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Pharmacology & Pharmacy ; Virology
研究领域[WOS]Pharmacology & Pharmacy ; Virology
关键词[WOS]PHOSPHORAMIDATE PROTIDE TECHNOLOGY ; BIOLOGICAL EVALUATION ; ANTIVIRAL ACTIVITY ; DNA CLEAVAGE ; A ANALOGS ; DERIVATIVES ; POTENCY ; PRODRUGS ; VIRUS ; D4T
英文摘要

Design and synthesis of nucleoside analogues have persistently attracted extensive interest because of their potential application in the field of antiviral therapy, and its study also receives additional impetus for improvement in the ProTide technology. Previous studies have made great strides in the design and discovery of monophosphorylated nucleoside analogues as potential kinase-independent antiretrovirals. In this work, a series of nucleoside phosphoramidates modified by distamycin analogues was synthesized and evaluated as nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-1-infected MT-4 and CEM cells, including variations in nucleoside, alkyl moiety, and the structure of distamycin analogues. These compounds exhibited modest potency with the EC50 value in the range of 1.3- to 6.5-fold lower than their corresponding parent drugs in MT-4 cells, which may be attributed to increasing intracellular availability due to the existence of distamycin analogue with favorable hydrophilic-lipophilic equilibrium. Meanwhile, the length of distamycin analogue was considered and assessed as an important factor that could affect antiviral activity and cytotoxicity. Enzymatic and metabolic stability studies have been performed in order to better understand the antiviral behavior of these compounds. The present work revealed the compounds to have a favorable and selective anti-HIV-1 activity in MT-4 and CEM cells, and helped to develop strategies for design and synthesis of effective monophosphorylated nucleoside analogues, which may be applied to antiretroviral research as NRTIs. (C) 2013 Elsevier B.V. All rights reserved.

语种英语
WOS记录号WOS:000331485900007
项目编号21372024 ; 21202005 ; 21232005 ; 21172016
资助机构National Nature Science Foundation of China
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/59863
专题北京大学药学院
北京大学口腔医学院_材料检测中心
作者单位1.Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
3.Xiamen Univ, Coll Chem & Chem Engn, Dept Chem, Xiamen 361005, Peoples R China
推荐引用方式
GB/T 7714
Li, Chao,Ma, Chunying,Zhang, Jin,et al. Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors[J]. ANTIVIRAL RESEARCH,2014,102:54-60.
APA Li, Chao.,Ma, Chunying.,Zhang, Jin.,Qian, Ning.,Ding, Jingjing.,...&Zhao, Yufen.(2014).Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors.ANTIVIRAL RESEARCH,102,54-60.
MLA Li, Chao,et al."Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors".ANTIVIRAL RESEARCH 102(2014):54-60.
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