Fluorophosphonylated Nucleoside Derivatives as New Series of Thymidine Phosphorylase Multisubstrate Inhibitors

Abstract

The synthesis of new class of potential TPase inhibitors containing a difluoromethylphosphonate function as phosphate mimic is reported. This new series was prepared from a readily available fluorinated building block in few steps. Two series were evaluated as potential inhibitors: a linear series and a conformational constrained series. The activity of these multisubstrate inhibitors depends on the size of the spacer introduced between the pyrimidine ring and the phosphonate function. Best results were observed from triazolyl derivatives, easily obtained from propargylthymine and corresponding azides.

Multicomponent Click Synthesis of New 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases: Promising Acidic Corrosion Inhibitors for Steel

“…Monopropargyl pyrimidine nucleobases (uracil and thymine) are versatile building blocks for the synthesis of biologically relevant 1,2,3-triazoles [11]. They are generally used as starting material for the synthesis of triazole nucleosides [12][13][14][15][16][17][18][19], triazole nucleotides [20][21][22][23], oxiconazole analogues [24], nucleopeptides [25], inhibitors of human topoisomerase type II [26], and nucleoamino oxyacids [27]. Further, these propargyl nucleobases are also used in the synthesis of organogels [28], and as corrosion inhibitors [29].…”

Molecular modeling study of the thymidine phosphorylase inhibitor by SBDD and classical QSAR analysis

“…All compounds which were synthesized to develop the potent HTP inhibitor were reported in our previous papers [10,11]. Since then, several other HTP inhibitors have been developed [12][13][14][15][16][17][18][19][20], but TPI is still assumed to be the most potent HTP inhibitor. …”

A straightforward synthesis of well‐defined difluorophosphonylated terminated poly(ε‐caprolactone) for grafting onto iron oxide magnetic nanoparticles

“…1,4 However, the low pKa 2 value of phosphonic acid and the hydrolyzable phosphate or phosphoric acid could limit their use for medicinal applications. 5 To address these issues, the difluoromethylphosphonate (or difluorophosphonate, pCF 2 ) derivatives and difluorophosphonic acid have been considered as interesting candidates for pharmaceutical and biomaterials applications [5][6][7][8][9] due to their resistance toward enzyme degradation and water hydrolysis. 6,[10][11][12] Additionally, difluorophosphonic acid is a stronger acid than phosphonic or phosphoric acids.…”

“…5 To address these issues, the difluoromethylphosphonate (or difluorophosphonate, pCF 2 ) derivatives and difluorophosphonic acid have been considered as interesting candidates for pharmaceutical and biomaterials applications [5][6][7][8][9] due to their resistance toward enzyme degradation and water hydrolysis. 6,[10][11][12] Additionally, difluorophosphonic acid is a stronger acid than phosphonic or phosphoric acids. 10 As long-standing interest in our laboratory, we were pioneers in the development of pCF 2 -functionalized monomers and polymers as potent self etching primers for dental applications.…”

“…Moreover, block copolymer based on PCL bearing phosphorous groups have been synthesized. 24 Beside the interest of pCF 2 function in term of stability, 5,6,[10][11][12][13] to the best of our knowledge, no previous studies have been reported on the synthesis of pCF 2 -functionalized PCL.…”