Chemistry of bisSATE Mononucleotide Prodrugs

Abstract

On the basis of AZT as a nucleosidic model, the protocols herein describe the synthesis of various bis(S-acyl-2-thioethyl) phosphotriester derivatives. These compounds, bearing transient phosphate-protecting groups, were designed to liberate the corresponding 5'-mononucleotide inside the cell through an esterase-mediated activation process. Two synthetic approaches are presented using either phosphoramidite intermediates or esterification of a nucleoside 5'-monophosphate.

Dissecting the role of protein phosphorylation: a chemical biology toolbox

“…Fully phospho-protected peptides were synthesized by coupling the building block Fmoc-Thr[PO(OH)(OPOM)]-OH and, prior to cleavage, “POMylation” of the free phosphoric acid group with iodomethylpivalate (POMI) and DIEA was performed in order to mask the negative charge. Adopting methods developed for mononucleotide prodrugs, 85 Imbach and colleagues installed S-acyl-2-thioethyl (SATE) groups on phosphotyrosine. 36 The bis(S-pivaloyl-2-thioethyl)-protected (bis( t BuSATE)) phosphotyrosine was used in the solution-phase synthesis of a Leu-enkephalinamide derivative with increased stability to cleavage by leucine aminopeptidase (Table 1, entry 9).…”