Na. Vandraanen et al., INFLUENCE OF STEREOCHEMISTRY ON ANTIVIRAL ACTIVITIES AND RESISTANCE PROFILES OF DIDEOXYCYTIDINE NUCLEOSIDES, Antimicrobial agents and chemotherapy, 38(4), 1994, pp. 868-871
Beta-L-2',3'-Dideoxycytidine (beta-L-ddC) and beta-L-5-fluoro-2',3'-di
deoxycytidine (5-F-beta-L-ddC) were prepared and shown to have potent
activity against human immunodeficiency virus type 1 (HIV-1) and hepat
itis B virus (HBV). These compounds were compared with beta-D-2',3'-di
deoxycytidine (beta-D-ddC) and two beta-L-oxathiolane nucleosides (bet
a-L-3'-thio-2',3'-dideoxycytidine and beta-L-5-fluoro-3'-thio-2',3'-di
deoxycytidine) in terms of anti-HIV and anti-HBV activity, cytotoxicit
y, and development of HIV-1 resistance. Compared with beta-D-ddC, the
beta-L-dideoxycytidine nucleosides had similar anti-HIV-1 activities,
significantly greater anti-HBV activities, and decreased toxicities to
a B-cell line, T-cell lines, and human bone marrow progenitor cells.
HIV-1 strains resistant to beta-D-ddC were susceptible to the beta-L-d
dC analogs. Compared with the beta-L-oxathiolane nucleosides, beta-L-d
dC and 5-F-beta-L-ddC had similar anti-HIV-1 activities, decreased ant
i-HBV activities, and greater toxicities to B- and T-cell lines and bo
ne marrow progenitor cells. There were similarities between the beta-L
-ddC and beta-L-oxathiolane nucleosides in the rate of development and
pattern of resistant HIV-1 selection. While the in vitro activity and
cytotoxicity profiles of the beta-L-ddC nucleosides differed from tho
se of the beta-D-ddC and beta-L-oxathiolane nucleosides, the data pres
ented herein suggest that the sugar configuration of a dideoxynucleosi
de analog may play a major role in the rate of development and the pat
tern of HIV-1 resistance.