Haloalkyl Phosphate Derivatives of AZT as Inhibitors of HIV: Studies in the Phosphate Region

Abstract

Novel haloalkyl phosphate derivatives of the anti-HIV nucleoside analogue AZT were prepared by phosphorochloridate chemistry. These materials were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral action, which varied greatly with the structure of the phosphate moiety. By comparison to simple dialkyl phosphates, which are inactive against HIV-1, the introduction of halogen atoms into the alkyl (phosphate) chains led to anti-HIV activity. Although halogen substitution in just one alkyl chain was sufficient for biological activity, substitution in the second alkyl chain further enhanced activity. Conversely, stabilization of the second chain, by conversion to a phosphonate, led to a reduction in activity. In one case, the diastereo-isomers resulting from mixed stereochemistry at the phosphate centre were separated, and found to differ in activity by one order of magnitude. Lastly, the bis(mono- and di-chloroethyl) phosphates were prepared and found to display moderate anti-HIV activity.

The ProTide Prodrug Technology: From the Concept to the Clinic

“…To enhance the intracellular cleavage of the haloalkyl masking groups, more haloalkyl phosphate masking groups with halogen atoms incorporated either on one or in both masking groups were used for making AZT monophosphate prodrugs. However, these prodrugs also displayed moderate antiviral activities . However, the use of haloalkyl groups in AraA and AraC monophosphates displayed significant increases in biological activity (Stage 1, Table ).…”

“…However, these prodrugs also displayed moderate antiviral activities. 46 However, the use of haloalkyl groups in AraA and AraC monophosphates displayed significant increases in biological activity (Stage 1, Table 1). 47 This increase in activity was mainly attributed to increased lipophilicity, resulting in better membrane permeability of the prodrug.…”

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

“…[18] Attempts to boost the anti-HIV activity of these haloalkyl phosphate triesters by changing the degree or nature of halogenation were generally unsuccessful. [19] However, haloalkyl triester derivatives of araA (6) and araC (7) did display enhanced biological activities. [20] Interestingly, the biological activities of araA and araC derivatives correlated to the lipophilicity of the phosphate triester pro- drugs.…”

Synthesis of Mimics to 5-(2″-thienyl)-2′,3′-β-Dideoxyuridine Triphosphate

“…Several reports describe the use of nucleoside monophosphate prodrugs that have been made more lipophilic by preparation of various 5'-O-phosphonates (Henin et el., 1991;McGuigan et a/., 1992;Sergheraert et a/., 1993;McGuigan et a/., 1994;Pannecoucke et a/., 1994) and 5-'O-phosphoramidates (McGuigan et el., 1993a; McGuigan et a/., 1!;l93b). Nucleoside prodrugs have also been designed by 5'-O-esterification (Aggarwal et a/., 1990;Sharma et el., 1993).…”