Design and synthesis of a reagent for solid-phase incorporation of the phosphothreonine mimetic (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) into peptides in a bio-reversible phosphonyl-bis-pivaloyloxymethyl (POM) prodrug form

Abstract

Reported herein are the synthesis and solid-phase peptide incorporation of N-Fmoc-(2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid bis-pivaloyloxymethyl phopshoryl ester [Fmoc-Pmab(POM)2-OH, 2] as a phosphatase-stable phosphothreonine (pThr) mimetic bearing orthogonal protection suitable for the synthesis of Pmab-containing peptides having bio-reversible protection of the phosphonic acid moiety. This represents the first report of a bio-reversibly protected pThr mimetic in a form suitable for facile solid-phase peptide synthesis.

Phosphonopeptides containing free phosphonic groups: recent advances

“…13), appeared to be potent effectors of this cell cycle regulatory protein and may serve as a tool to study its role in cancerogenesis. [62][63][64][65] Masking the phosphonate moiety of peptide 43 by esterase labile pivaloyloxymethyl groups provided interesting prodrug. 63 The major challenge in the studies on these mimetics is their synthesis.…”

“…This compound was asymmetrically reduced using chiral catalyst and nally converted into compound 48 suitable for introduction into peptide chain. 64 Preparation of the desired peptides was achieved easily by using classical procedures of both liquid-and solid-phase peptide syntheses.…”

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…This prodrug exhibited approximately a 20-fold increase in activity over the free acid [233]. A recent report on phosphothreonine analogs targeted towards Plk1 also has relied upon a bis-POM strategy [234]. …”

Selective Isolation of Myosin Subfragment-1 with a DNA-Polyoxovanadate Bioconjugate

“…Functionalization via covalent grafting of organic functional groups allows POMs to tune their redox ability, acidity, and solubility, together with a potential modulation of essential features, e.g., stability, bioavailability, and recognition capability. , A lot of POMs containing compounds have been prepared with POMs retaining their structural integrity, including organonitrogen, organosilyl, organophosphonyl, and oxocarbon derivatives of POMs. The heteropolytungstates [α 2 -P 2 W 17 O 61 (SnR)] 7 has been reported with an alkyltin group with promising antitumor activities .…”