Once the agent is inside the cell. Despite the fact that various common prodrug methods have already been for phosphonic acids (Schultz 2003; Hecker and Erion 2008), you’ll find couple of reports detailing incorporation of those functionalities into protected amino acid derivatives that happen to be amenable to solid-phase peptide synthesis. Recent examples of your latter contain the application of 5′-nitrofuryl-2′-methyl N-(4″-chlorobutyl)phosphonamido ester prodrug strategy towards the pTyr mimetic difluorophosphonomethylphenylalanine (F2Pmp) (Boutselis et al. 2007) and to the pSer mimetic, difluorophosphonoaminobutyric acid (Arrendale et al. 2012). In these two instances, the prodrug-protected reagents have been employed to prepare dipeptides for examination in entire cell studies. The use of these reagents for the solid-phase synthesis of longer peptides is potentially limited by chemical instability from the phosphonamido group to repetitive cycles of piperidine remedy required for Fmoc-based solid-phase protocols (Boutselis et al. 2007). In the broader sense, there is a paucity of reagents readily available for the solid-phase synthesis of polypeptides containing prodrug-protected pThr mimetics. The pivaloyloxymethyl (POM) group is definitely an esterase-labile moiety which has been broadly applied to phosphoryl prodrug protection of nucleotides (Hecker and Erion 2008) and phosphate and phosphonic acid functionality in small molecules and peptide mimetics (Stankovic et al. 1997; Mandal et al. 2009; Mandal et al. 2011; Zhao and Etzkorn 2007). Having said that, in spite of its usefulness in these latter contexts, there are actually no prior reports of polypeptides containing pThr, pSer or their phosphonic acid-based mimetics, bearing POM protection. Offered the significance of pThr within a significant quantity of biological processes (Elia and Yaffe 2005), a reagent that would permit the solid-phase synthesis of polypeptides containing POM-protected pThr mimetics will be very desirable.SM-102 Formula We had previously reported the preparation of N-Fmoc-(2S,3R)-2-amino-3-methyl-4phosphonobutyric acid bis-tert-butyl phopshoryl ester [Fmoc-Pmab(But2)-OH, 1, Fig.Formula of 178432-48-9 1] as a hydrolytically-stable pThr mimetic bearing orthogonal protection suitable for the standard Fmoc-based synthesis of peptides containing Pmab.PMID:23600560 Nevertheless this reagent yields peptides in which the Pmab residue has its phosphonic acid moiety within the cost-free di-anionic type (Liu et al. 2009). To date, there happen to be no reports of Pmab suitably derivatized for the solid-phase synthesis of polypeptides that maintained the phosphonic acid inside a prodrug-protected kind. In the existing paper we describe the first preparation of Fmoc-Pmab having the phosphonic acid group masked as its POM bis-esters [Fmoc-Pmab(POM)2-OH, 2, Fig. 1] and demonstrate its use in the solid-phase synthesis of a peptide bearing full POM protection of your Pmab residue.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMaterials and methodsGeneral approaches All experiments involving moisture-sensitive compounds have been performed under anhydrous situations. Fmoc-Ser(Trt)-OH, and Fmoc-His(Mtt)-OH were purchased from NovaChioChem. All solvents were bought in anhydrous kind (Aldrich) and utilized directly. Analytical TLCs have been performed making use of Analtech precoated plates (Uniplate, silica gel GHLF, 250 nm) containing a fluorescence indicator. NMR spectra have been recorded working with a Varian Inova 400 MHz spectrometer. Coupling constants are reported in hertz, and peak shifts are reported in ?(ppm) relative to TMS. Low-resolu.
