Syntheses of 1-[2-(Phosphonomethoxy)Alkyl]Thymine Monophosphates and an Evaluation of their Inhibitory Activity Toward Human Thymidine Phosphorylase

Abstract

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).

Keywords:

• Acyclic nucleoside phosphonates
• phosphorylation
• human thymidine phosphorylase
• phosphorolysis
• pyrimidine

Acknowledgments

This study has been done as a part of Research Project #Z 40550506 of the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and the Centre of New Antivirals and Antineoplastics’ Project 1M0508 supported by the Ministry of Education, Youth and Sports of the Czech Republic. For helpful discussions, the authors thank Dr. Zdeněk Točík.