Metabolism of 2′,3′-Dideoxy-2′,3′-Didehydro-β- l (−)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus β- d (+) Nucleoside Analogs In Vitro

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Abstract
2′,3′-Dideoxy-2′,3′-didehydro-β- l (−)-5-fluorocytidine [ l (−)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of l (−)Fd4C plus 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T, or stavudine) or 3′-azido-3′-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with l (−)Fd4C in combination with 2′,3′-dideoxycytidine (ddC, or zalcitabine) or 2′,3′-dideoxyinosine (ddI, or didanosine). This β- l (−) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 μM. As we previously reported for other β- l (−) nucleoside analogs, l (−)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the K m is 100 μM. l (−)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also, l (−)Fd4C was not a substrate for deoxycytidine deaminase. l (−)Fd4C 5′-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by l (−)Fd4C in two-drug combinations favors the further development of l (−)Fd4C as an anti-HIV agent.

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