Synthesis and biological evaluation of 2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine (D4FC) analogues: discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase.
Synthesis and biological evaluation of 2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine (D4FC) analogues: discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase.
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2,3-二脱氢-2,3-双脱氧-5-氟胞苷 (D4FC) 类似物的合成和生物学评价：发现对 HIV-1 逆转录酶具有有效抑制活性的碳环核苷三磷酸。
DOI：
10.1021/jm980510s
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发表时间：
1999
影响因子：
7.3
通讯作者：
Schinazi,RF
中科院分区：
文献类型：
--
作者：
Shi,J;McAtee,JJ;SchlueterWirtz,S;Tharnish,P;Juodawlkis,A;Liotta,DC;Schinazi,RF
β-d-2 '，3'-二脱氧-2 '，3'-二脱氧-5-氟胞嘧啶核苷（β-d-D4 FC）是一种新型的抗人类免疫缺陷病毒（HIV）的药物，它的发现使我们合成了一系列具有更高选择性和糖苷键稳定性的β-d-D4 FC类似物和衍生物。对合成的-D4 FC类似物在各种细胞中的抗HIV-1活性、抗癌活性和细胞毒性进行了评价。生物学数据表明，β-d-D4 FC被溴（6c）和碘（6d）5位取代导致抗病毒活性丧失，并且d-D4 FC的α-双链体（7a）也没有活性。d-D4 FC的5-氟尿嘧啶类似物（6和7 b）的效力低于母体化合物，但细胞毒性高于母体化合物，而β-l-D4 FU（11）显示出有效的抗HIV-1活性和细胞毒性。β-d-D4 FC的N4-和5 '-O-酰基衍生物（17，15 a −c）显示出与β-d-D4 FC相当的抗病毒活性。相比之下，β-d-D4 FC的N4-异丙基衍生物（20）即使在100 μM时也没有抗HIV-1的活性。D4 FC的碳环类似物（26 a，B）对HIV-1的活性较弱，对多种细胞无毒性。碳环核苷的三磷酸（27 a，B）在亚微摩尔浓度下表现出对重组HIV-1逆转录酶的有效抑制活性。在作为潜在抗癌剂测试的化合物中，β-d-、α-d-和β-l-D4 FU（6 b、7 b、11）显示出对大鼠神经胶质瘤的抑制活性和对人肺癌、淋巴母细胞样瘤和皮肤黑素瘤细胞的适度活性。
The discovery of a novel cytosine nucleoside, β-d-2‘,3‘-didehydro-2‘,3‘-dideoxy-5-fluorocytidine (d-D4FC), as a potent antihuman immunodeficiency virus (HIV) agent led us to synthesize a series of analogues and derivatives of β-d-D4FC that could be more selective and also possess increased glycosidic bond stability. The synthesizedd-D4FC analogues were evaluated for anti-HIV-1 activity, anticancer activity, and cytotoxicity in various cells. The biological data demonstrated that the 5-substitution of β-d-D4FC with bromine (6c) and iodine (6d) resulted in the loss of antiviral activity, and the α-danomer (7a) ofd-D4FC was also devoid of activity. The 5-fluorouracil analogues (6band7b) ofd-D4FC were less potent and more cytotoxic than the parent compound, whereas the β-l-D4FU (11) showed both potent anti-HIV-1 activity and cytotoxicity.N4- and 5‘-O-acyl derivatives (17,15a−c) of β-d-D4FC exhibited comparable antiviral activity to β-d-D4FC. In contrast, theN4-isopropyl derivative (20) of β-d-D4FC was not active against HIV-1, even at 100 μM. The carbocyclic analogues (26a,b) of D4FC demonstrated weak activity against HIV-1 and no toxicity in various cells. The triphosphates (27a,b) of the carbocyclic nucleosides demonstrated potent inhibitory activity against recombinant HIV-1 reverse transcriptase at submicromolar concentrations. Of the compounds tested as potential anticancer agents, β-d-, α-d-, and β-l-D4FU (6b,7b,11) showed inhibitory activity against rat glioma and modest activity against human lung carcinoma, lymphoblastoid, and skin melanoma cells.