Syntheses of 1-[2-(Phosphonomethoxy)Alkyl] thymine monophosphates and an evaluation of their inhibitory activity toward human thymidine phosphorylase.

A series of new monophosphates of 1-[2-(phosphonomethoxy)alkyl]thymines, such as PMPTp(,) 3-MeO-PMPTp, HPMPTp, and FPMPTp, were synthesized and tested for their ability to inhibit human thymidine phosphorylase. Kinetic measurements of enzyme activity were performed using thymidine and inorganic phosphate as the substrates. The data show that some monophosphates provide a considerable increase of the multisubstrate inhibitory effect. The highest inhibitory potency was found with (R)-FPMPTp 4c (K (i) (dT) = 4.09 ± 0.47 µM, K (i)(P(i)) = 2.13 ± 0.29 µM) and (R) 3-MeO-PMPTp 4d (K (i) (dT) = 5.78 ± 0.71 µM, K (i)(P(i)) = 2.71 ± 0.37 µM).