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学科主题: 药学
题名:
Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors
作者: 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
发表日期: 2014-02-01
DOI: 10.1016/j.antiviral.2013.12.002
卷: 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
所属项目编号: 21372024 ; 21202005 ; 21232005 ; 21172016
项目资助者: National Nature Science Foundation of China
WOS记录号: WOS:000331485900007
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59863
Appears in Collections:北京大学药学院_期刊论文

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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

Recommended Citation:
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.
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