Nucleoside analogs constitute an important class of drugs, as they are the basis for most treatment strategies against extremely important human pathogens such as herpes simplex virus (HSV), varicella zoster virus (VZV), human cytomegalovirus (HCMV), human immunodeficiency virus (HIV) hepatitis C virus (HCV), hepatitis B virus (HBV) and also cancer. Among them 2’-halogenated nucleosides analogs have drawn special attention which led to the approval of Gemcitabine (2’-deoxy, 2’,2’-difluorocytidine) and Clofarabine (2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine) for cancer along with Sofosbuvir, a monophosphate prodrug of 2’-deoxy, 2’-β-methyl-2’-α-F uridine, for the treatment of HCV. In our search for new antivirals, we studied in details the influence of different combination of halogens at the 2’-position by preparing and evaluating 2’-β-Cl,2’-α-F (1), 2’-β-Br,2’-α-F- (2), 2’-α-Cl,2’-β-F (3), 2’-α-Br,2’-β-F- (4), 2’-diCl (5), 2’-diBr (6) and 2’-α-Br,2’-β-Cl (7) uridine monophosphate prodrugs. Synthesis of these compound was either achieved from deoxyribonolactone or by using stereo-selective aldolisation and halogenation reactions. Interestingly, all of the dihalogenated compounds displayed selective inhibition of HCV (GT1b) in a subgenomic HCV replicon system.

Synthetic efforts towards the preparation of 2’-dihalogenated nucleotide prodrugs

2019 Spring National Meeting

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