Novel alkyl hydrogen phosphonate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridite chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation has revealed the compounds to have a pronounced and selective antiviral action. Short-chain (C1-C7) alkyl derivatives are more potent than the parent hydrogen phosphonate, whilst one long-chain (C18) compound is less active. In an assay that demonstrates the toxicity of the parent drug AZT, the alkyl H-phosphonates appear to be less cytotoxic, whilst retaining full antiviral activity. Lastly, the compounds are all poorly active in a cell line (JM) that is poorly responsive to AZT, indicating that they act as depot forms of the nucleoside rather than of the free nucleotide.
Properties of Some Long Chain Alkyl Derivatives of Betaine.