Phosphate derivatives of AZT display enhanced selectivity of action against HIV1 by comparison to the parent nucleoside

Abstract

Novel phosphate derivatives of the and-HIV nucleoside anulogue AZT have been prepared by phosphorochloridate chemistry. In particular, phosphates carrying ester-containing side-chains are described. These materials arc designed 10 act as membrane-soluble prodrugsof the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anliviral activity. In several cases the phosphate derivatives are more seieclive in their aclhl than the parent nucleoside AZT. In particular, this arises from the low toxicity of the phosphate pro-drugs by comparison to AZT. These data support the suggestion thal the phosphate derivatives exert their biological effects via intracellular release of the nuclcotide forms, and suggests that such pro-drug forms may be worthy of further study.

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

“…In this report McGuigan stated: “If these in vitro findings could be translated into a demonstrable in vivo advantage, such phosphate pro-drugs could have merit as candidates for clinical development.” 138 This was clearly an anticipation of what would have happened 25 years later. His investigations underlaid the importance of the masked phosphate approach, and had significant implications for what became the future design of chemotherapeutic NAs.…”

“…Continuing to explore different structures, the phosphorus center was then masked with an ester-containing group in combination with either a simple alkyl moiety or a trichloroethyl group or another ester-containing group. 138 The results of these investigations revealed the presence of two ester-substituted groups enhances activity relative to having only one substituted group. Furthermore, suggesting that a trihaloethyl group may substitute for an ester-containing group but with reduced potency.…”

Synthesis and Anti-HIV Activity of Alkyl Steroidal 3′-Azido-3′-deoxythymidin-5′-yl Phosphotriesters as Prodrugs of AZT

“…In recent years a similar prodrug approach of nucleotides has been reported. [14][15][16][17][18][19][20] While simple dialkyl phosphotriesters16 of AZT were found to be inactive, haloalkyl l6 and other lipophilic long chain alkyl phosphotriesters 18,19 of AZT showed comparable activity with that of AZT.…”

The purification and characterization of deoxycytidine kinase from calf thymus

“…A number of researchers have demonstrated that the phosphate group on the nucleoside analogs has the potential to be a new antivirus drug with antiviral activity (McGuigan et al 1992). Thus some emphasis has been placed on developing a commercial and simple way of synthesizing the monophosphate derivative of the nucleoside analog (Uckum et al 2005;Kitade 1997).…”