Prodrugs of pyrophosphates and bisphosphonates: disguising phosphorus oxyanions

Abstract

Pyrophosphates have important functions in living systems and thus pyrophosphate-containing molecules and their more stable bisphosphonate analogues have the potential to be used as drugs for treating many diseases including cancer and viral infections. Both pyrophosphates and bisphosphonates are polyanionic at physiological pH and, whilst this is essential for their biological activity, it also limits their use as therapeutic agents. In particular, the high negative charge density of these compounds prohibits cell entry other than by endocytosis, prevents transcellular oral absorption and causes sequestration to bone. Therefore, prodrug strategies have been developed to temporarily disguise the charges of these compounds. This review examines the various systems that have been used to mask the phosphorus-containing moieties of pyrophosphates and bisphosphonates and also illustrates the utility of such prodrugs.

Fig. 1. (A) General structures of pyrophosphates and bisphosphonates; (B) some biologically relevant pyrophosphates.

Fig. 2. Acyl NDP prodrugs studied by Huynh-Dinh and coworkers.

Fig. 3. (A) Hydrolysis pathway of cycloSal NMP prodrugs. (B) Major hydrolysis pathway of cycloSal AZTDP prodrugs.

Fig. 4. Bis(acyloxybenzyl)NDP prodrugs studied by Meier and coworkers.

Scheme 1. Mechanism of activation of DiPPro-nucleotides.

Fig. 5. Bis(benzoyloxybenzyl) NDP prodrugs studied by Meier and coworkers.

Fig. 6. Non-symmetric bis(acyloxybenzyl) NDP prodrugs studied by Meier and coworkers.

Fig. 7. Compounds to which the diPPro concept has been applied.

Fig. 8. (A) Acetoxybenzyl 5-PP-myo-InsP₅ prodrugs studied by Jessen and coworkers; (B) undesired degradation pathways of (partially unmasked) prodrug 25a.

Fig. 9. Examples of (A) non-nitrogenous bisphosphonates and (B) nitrogenous bisphosphonates.

Fig. 10. Alkyl esters of clodronate and etidronate studied by Vepsäläinen and coworkers.

Fig. 11. Aryl esters studied by Lecouvey and coworkers.

Fig. 12. Cyclic esters of risedronate studied by Pavlov et al.

Scheme 2. Mechanism of activation of (A) POM and (B) POC ester prodrugs.

Fig. 13. POM esters of clodronate and etidronate acetate studied by Vepsäläinen and coworkers.

Fig. 14. POM esters studied by Wiemer and coworkers.

Fig. 15. POM and POC esters studied by Zhang et al.

Fig. 16. POM esters studied by Tanaka and coworkers.

Fig. 17. POM and methyl esters studied by Wiemer and coworkers.

Fig. 18. Clodronate anhydrides studied by Ahlmark et al.

Scheme 3. Partial hydrolysis of a cyclic dimer of clodronate studied by Vepsäläinen and coworkers.

Scheme 4. Mechanism of activation of bisphosphonamidate esters studied by Freel Meyers and coworkers.

Fig. 19. Clinically approved POM and POC prodrugs of nucleotide analogues.

Scheme 5. Mechanism of deprotection of the SATE prodrug IDX184.

Scheme 6. Mechanism of deprotection of the ProTide Sofosbuvir.

Fig. 20. Various other clinically trialled phosph(on)ate prodrugs.

Emma Rudge

Alex H. Y. Chan

Finian Leeper