Synthesis and in vitro activities of a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via an octadecylglycerol residue
Synthesis and in vitro activities of a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via an octadecylglycerol residue
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DOI：
10.1016/j.bmc.2008.10.081
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Schwendener, Reto A.
中科院分区：
文献类型：
--
作者：
Schott, Herbert;Hamprecht, Klaus;Schwendener, Reto A.
为制备齐多夫定（AZT）与膦甲酸（PFA）通过亲脂性十八烷基甘油残基连接的新型抗病毒双药，我们将3-O-十八烷基-sn-甘油与AZT通过膦酸酯法缩合得到1-O-4-单甲氧基三苯甲基-3-O-十八烷基-sn-甘油-2-膦酸氢酯。将纯化的缩合产物脱三苯甲基，得到3 ′-叠氮基-3 ′-脱氧胸苷基-（5 ′-> 2-O）-3-O-十八烷基-sn-甘油，然后用（乙氧基羰基）二氯化磷处理。所得的3 ′-叠氮基-3 ′-脱氧-胸苷基-（5 ′-> 2）-3-O-十八烷基-sn-甘油-1-O-（乙氧羰基）膦酸酯通过制备型RP-18柱色谱法纯化。膦甲酸乙酯残基经碱裂解后得到抗病毒双重药物3 ′-叠氮基-3 ′-脱氧胸苷基-（5 ′-> 2-O）-3-O-十八烷基-sn-甘油-1-O-膦甲酸三钠盐（AZT-脂质-PFA）。以克规模进行的五步合成的总产率为约30%。根据推测的途径，AZT-脂质-PFA可以裂解以产生不同抗病毒化合物的混合物，例如AZT、AZT-5 '-单磷酸、十八烷基甘油-AZT、PFA和十八烷基甘油-PFA，可能产生累加和/或协同抗病毒作用。体外研究表明，双链药物对HIV，特别是对HSV和HCMV的耐药菌株和临床分离株具有抗病毒活性。AZT-脂质-PFA对HIV的E（50）值在170和200 nM之间。通过空斑减少试验确定的对高度无环鸟苷（ACV）耐药HSV分离株的半数最大抑制剂量（IC（50））范围为1.87和4.59 μ M。使用更昔洛韦（GCV）敏感、GCV耐药和药物交叉耐药HCMV株，AZT-脂质-PFA的IC（50）值在2.78和1.18 μ M之间。关于PFA，在多药耐药HCMV毒株上测定的AZT-脂质-PFA的IC（50）值比PFA低约90倍，表明双链药物具有上级抗病毒作用。(C)2008爱思唯尔有限公司保留所有权利。
To prepare a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via a lipophilic octadecylglycerol residue we condensed 1-O-4-monomethoxytrityl-3-O-octadecyl-sn-glycerol-2-hydrogenphosphonate obtained from 3-O-octadecyl-sn-glycerol with AZT by the phosphonate method. The purified condensation product was de-tritylated resulting in 3'-azido-3'-deoxythymidylyl-(5' -> 2-O)-3-O-octadecyl-sn-glycerol, followed by treatment with (ethoxycarbonyl) phosphoric dichloride. The resulting 3'-azido-3'-deoxy-thymidylyl-(5' -> 2)-3-O-octadecyl-sn-glycerol-1-O-(ethoxycarbonyl) phosphonate was purified by preparative RP-18 column chromatography. The antiviral duplex drug 3'-azido-3'-deoxythymidylyl-(5' -> 2-O)-3-O-octadecyl-sn-glycerol-1-O-phosphonoformate trisodium salt (AZT-lipid-PFA) was obtained after alkaline cleavage of the phosphonoformate ethylester residue. The overall yield of the five step synthesis performed at gram scale was about 30%. According to a supposed pathway AZT-lipid-PFA could be cleaved to yield a mixture of different antiviral compounds such as AZT, AZT-5'-monophosphate, octadecylglycerol-AZT, PFA and octadecylglycerol-PFA, possibly producing additive and/or synergistic antiviral effects. In vitro studies showed that the duplex drug exhibits antiviral activities against HIV and especially against drug-resistant strains and clinical isolates of HSV and HCMV. The E(50) values of AZT-lipid-PFA against HIV ranged between 170 and 200 nM. The half-maximal inhibitory doses (IC(50)) against highly acyclovir (ACV)-resistant HSV isolates determined by a plaque reduction assay ranged between 1.87 and 4.59 mu M. Using ganciclovir (GCV)-sensitive, GCV resistant and drug cross-resistant HCMV strains the IC(50)-values of AZT-lipid-PFA were between 2.78 and 1.18 mu M. With regard to PFA, the IC(50)-value of AZT-lipid-PFA determined on a multi-drug-resistant HCMV strain was about 90-fold lower than that of PFA, demonstrating the superior antiviral effect of the duplex-drug. (C) 2008 Elsevier Ltd. All rights reserved.