合成及 3'-氟（或氯）和 2',3'-二氟 2',3'-二脱氧核苷类似物对乙型肝炎和丙型肝炎病毒的体外抗病毒活性。

Synthesis and in vitro antiviral activities of 3'-fluoro (or chloro) and 2',3'-difluoro 2',3'-dideoxynucleoside analogs against hepatitis B and C viruses.

机构信息

Department of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, University of Alberta, Edmonton, AB, Canada T6G 2H7.

出版信息

Bioorg Med Chem. 2010 Nov 1;18(21):7542-7. doi: 10.1016/j.bmc.2010.08.048. Epub 2010 Sep 23.

DOI:10.1016/j.bmc.2010.08.048

PMID:20869253

Abstract

Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) lead to serious liver diseases worldwide. Co-infection with HBV and HCV is very common and is associated with increased risk of liver pathogenesis, liver cancer, and liver failure. Several 5-substituted 3'-fluoro (or chloro) (1-4, 6, 7, 17-19) and 2',3'-difluoro 2',3'-dideoxynucleosides (15 and 16) were synthesized and evaluated for in vitro antiviral activities against duck hepatitis B virus (DHBV), human hepatitis B virus, and hepatitis C virus. Of these compounds 4, 7, 17, and 19 demonstrated moderate anti-HBV activity, and 2, 4, 7, 8, and 19 were weak inhibitors of HCV. Although 5-iodo derivative (7) was most inhibitory against HCV, it exhibited a reduction in cellular RNA levels in Huh-7 cells. The 5-hydroxymethyl-3'-fluoro-2',3'-dideoxyuridine (4) and 1-(3-chloro-2,3-dideoxy-β-d-erythro-pentofuranosyl)-5-fluorouracil (19) provided the most inhibition of both viruses without cytotoxicity.

摘要

慢性乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染可导致全球严重的肝脏疾病。HBV 和 HCV 的合并感染非常常见，并且与肝脏发病机制、肝癌和肝功能衰竭的风险增加相关。已经合成了几种 5-取代的 3'-氟（或氯）（1-4、6、7、17-19）和 2'，3'-二氟 2'，3'-二脱氧核苷（15 和 16），并评估了它们对鸭乙型肝炎病毒（DHBV）、人乙型肝炎病毒和丙型肝炎病毒的体外抗病毒活性。这些化合物中，4、7、17 和 19 对 HBV 表现出中等的抗活性，而 2、4、7、8 和 19 对 HCV 具有弱抑制作用。尽管 5-碘代衍生物（7）对 HCV 的抑制作用最强，但它在 Huh-7 细胞中降低了细胞 RNA 水平。5-羟甲基-3'-氟-2'，3'-二脱氧尿苷（4）和 1-（3-氯-2,3-二脱氧-β-d-赤型戊呋喃糖基）-5-氟尿嘧啶（19）在没有细胞毒性的情况下对两种病毒提供了最强的抑制作用。