Triphosphate Prodrugs of the Anti-HIV-Active Compound 3'-Deoxy-3'-fluorothymidine (FLT).
Simon WeisingStefan WeberDominique ScholsChris MeierPublished in: Journal of medicinal chemistry (2022)
3'-Fluoro-3'-deoxythymidine (FLT) was identified as one of the most potent inhibitors of human immunodeficiency virus (HIV) replication. However, FLT also showed severe toxicity so that it was abundant as a potential chemotherapeutic agent. Here, we describe various triphosphate prodrugs of FLT aiming for (a) a bypass of all phosphorylation steps needed to convert the nucleoside analogue into its triphosphate (TP) form, (b) an intracellular delivery of hydrolytically and enzymatically stable triphosphate derivatives, and (c) increasing the selectivity for HIV-RT vs three cellular DNA polymerases including the mitochondrial DNA polymerase γ. γ-Alkylated FLTTP compounds fulfill all of these requirements because these compounds proved highly resistant to dephosphorylation and showed strong selectivity for HIV-RT. Moreover, a prodrug form of these compounds proved to be nontoxic in CEM cells.
Keyphrases
- human immunodeficiency virus
- antiretroviral therapy
- hiv infected
- hepatitis c virus
- hiv positive
- acute myeloid leukemia
- hiv aids
- hiv testing
- mitochondrial dna
- tyrosine kinase
- copy number
- oxidative stress
- induced apoptosis
- circulating tumor
- early onset
- south africa
- reactive oxygen species
- computed tomography
- dna methylation
- structural basis
- cell cycle arrest
- cell free
- drug induced
- cell proliferation