title: Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors.
abstract: 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.
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China. Electronic address: lichao@mail.buct.edu.cn.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: qiao_group@163.com.
authors.forename: Renzhong
authors.initials: R
authors.lastname: Qiao
authors.affiliation: Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, PR China.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000302:isolation & purification*; D002460:Cell Line; D004214:Distamycins / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D009705:Nucleosides / Q000737:chemistry* / Q000302:isolation & purification*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification*
chemical_list: D019380:Anti-HIV Agents; D004214:Distamycins; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C030000:stallimycin; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Anti-HIV; Antiretrovirals; Distamycin; Nucleoside analogue; ProTide