Design of novel derivatives of phosphonoformate (Foscarnet) as prodrugs and antiviral agents.

Phosphonoformate (PFA) is an effective antiviral agent that is used clinically in AIDS chemotherapy under the names of Foscarnet and Foscavir.1 Although the primary indication is AIDS-related human cytomegalovirus (HCMV) infection, PFA is also effective against HIV itself. PFA is proposed to act via inhibition of reverse transcriptase in HIV and DNA polymerase in herpes simplex virus (HSV) and HCMV, by blocking the pyrophosphate binding site in these enzymes. PFA is remarkable in being an analogue of the ubiquitous pyrophosphate, yet acting as a drug with a relatively high therapeutic index. However, the efficacy of PFA is seriously impeded by poor bioavailability due to its polyanionic nature at physiological pH. Prodrug approaches have been investigated to circumvent problems associated with the bioavailability and permeability of PFA.2 These prodrug strategies have ranged from simple triester approaches to use of inventive bioreversible groups, but have largely applied the tactics used for simple phosphonate prodrugs to PFA. However, PFA is not a simple phosphonate. The juxtaposition of carbonyl and phosphoryl groups leads to complex reactivity that remains to be fully explored. Mechanistic studies have demonstrated competitive nucleophilic attack at P or C at neutral pH, which may lead to P-O, C-O, and P-C bond cleavage.3 Reactivity at phosphorus in PFA esters is orders of magnitude greater than for simple phosphonates. In PFA triesters, nucleophilic substitution at the carbonyl carbon can lead to P-C bond cleavage and ester group migration between C and P. The idiosyncratic reactivity of PFA esters strongly influences synthetic strategies and pro-drug design. Herein, we report design rationale, synthesis, and antiviral activity for a novel family of PFA diesters that allows inclusion of the PFA moiety within a variety of biomolecules.