Stability and Efficiency of Mixed Aryl Phosphonate Prodrugs.

A set of phosphonate prodrugs of a butyrophilin ligand was synthesized and evaluated for plasma stability and cellular activity. The mixed aryl acyloxy esters were prepared either via a standard sequence through the phosphonic acid chloride, or through the more recently reported, and more facile, triflate activation. In the best of cases, this class of prodrugs shows cellular potency similar to that of bis-acyloxyalkyl phosphonate prodrugs and plasma stability similar to that of aryl phosphonamidates. For example, {[((3E)-5-hydroxy-4-methylpent-3-en-1-yl) (naphthalen-2-yloxy)phosphoryl]oxy}methyl 2,2-dimethylpropanoate can activate BTN3A1 in K562 cells after just 15 minutes of exposure (at an EC50 value of 31 nm) and is only partially metabolized (60 % remaining) after 20 hours in human plasma. Other related novel analogues showed similar potency/stability profiles. Therefore, mixed aryl acyloxyalkyl phosphonate prodrugs are an exciting new strategy for the delivery of phosphonate-containing drugs.