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.
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.
Srivastav
Naveen C
NC
Department of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, University of Alberta, Edmonton, AB, Canada T6G 2H7.
Shakya
Neeraj
N
Mak
Michelle
M
Liang
Chao
C
Tyrrell
D Lorne J
DL
Agrawal
Babita
B
Kumar
Rakesh
R
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000378:metabolism; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D015611:Hepatitis B Virus, Duck / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D012367:RNA, Viral / Q000378:metabolism
D000998:Antiviral Agents; D004279:DNA, Viral; D015224:Dideoxynucleosides; D012367:RNA, Viral; C058924:3'-fluoro-2',3'-dideoxyuridine; C059513:2',3'-dideoxyuridine