Synthesis and Biological Evaluation of Phosphate Prodrugs of 4‐Phospho‐D ‐erythronohydroxamic Acid, an Inhibitor of 6‐Phosphogluconate Dehydrogenase

Abstract

We have previously reported the discovery of potent and selective inhibitors of 6-phosphogluconate dehydrogenase, the third enzyme of the phosphate pentose pathway, from Trypanosoma brucei, the causative organism of human African trypanosomiasis. These inhibitors were charged phosphate derivatives with restricted capacity to enter cells. Herein, we report the synthesis of five different classes of prodrugs: phosphoramidate; bis-S-acyl thioethyl esters (bis-SATE); bis-pivaloxymethyl (bis-POM); CycloSaligenyl; and phenyl, S-acyl thioethyl mixed phosphate esters (mix-SATE). Prodrugs were studied for stability and activity against the intact parasites. Most prodrugs caused inhibition of the growth of the parasites. The activity of the prodrugs against the parasites appeared to be related to their stability in aqueous buffer.

Thermodynamic characterization of substrate and inhibitor binding to Trypanosoma brucei 6‐phosphogluconate dehydrogenase

“…Thus compounds such as 5‐phospho‐ d ‐ribonate (5PR), 4‐phospho‐ d ‐erythronate (4PE) and 4‐phospho‐ d ‐erythronohydroxamate (4PEX) have been found to have a 73‐, 80‐ and 254‐fold selectivity for T. brucei 6PGDH, respectively [3,4]. Some recently developed 4PEX parent compounds with phosphate masking groups, which are able to deliver active compounds into parasites, show a good level of trypanotoxicity [5].…”

“…73-, 80-and 254-fold selectivity for T. brucei 6PGDH, respectively [3,4]. Some recently developed 4PEX parent compounds with phosphate masking groups, which are able to deliver active compounds into parasites, show a good level of trypanotoxicity [5].…”

Conformational changes associated with cofactor/substrate binding of 6-phosphogluconate dehydrogenase from Escherichia coli and Klebsiella pneumoniae: Implications for enzyme mechanism

“…Moreover, our structures also provide information for antibiotics development. Indeed, some inhibitors of Tb6PGDH have been prepared (Montin et al, 2007;Ruda et al, 2007).…”

Optimization of Ion‐Dependent Green Synthesis of Fmoc‐Amino Acids in Phosphate Buffer

“…To further investigate role of phosphate and to capture some intermediate state, 1 H Nuclear magnetic resonance (NMR) and 31 P NMR spectroscopy of L‐Phe and Fmoc‐Cl reaction in presence of deuterated phosphate buffer and 10% deuterated ethanol was carried. As we suspected involvement of phosphate buffer in this reaction, and thus any shift in 31 P NMR spectra of phosphate might indicate its involvement in reaction . First 1 H NMR spectra was recorded to confirm product formation and to capture intermediate state, if possible.…”