Phosphonate-containing peptide

Cleavage of the phosphonate allyl esters from Abu[PO(OAl)2]-peptide-resins is accomplished by treatment with Pd(PPh3)4 (50 °C, 5 h)[103l followed by acidolytic deprotection of the Abu[PO(OH)2]-peptide from the resin support. The viability of employing allyl phosphonate protection for phosphopeptide synthesis has been demonstrated by the Fmoc solid-phase synthesis (DIC/HOBt couplings) of several 6-9-mer Abu[PO(OH)2]-containing peptides and has been extended to the synthesis of a 19-mer caldneurin-related Abu[PO(OH)2]-peptide.[104 ... 

As an example of developments in the phosphorus-containing peptide field, the syntheses of (285), a tripeptidic (l-hydroxy-2-aminoalkyl)phosphonic acid, and some analogues, have been reported the compound (285) itself is a good inhibitor of human renin. ... 

The use of benzyl A-phosphonate (Fig. 16, 37) was illustrated with the synthesis of a 5-mer phosphoserine-containing peptide [146]. The reagent was activated by pivaloyl chloride in pyridine, followed by in situ oxidation with 1% iodine (w/v) in pyridine-water (98 2 v/v). Phosphoramidites are considered to be superior to the other phosphitylating reagents and have been extensively used for the synthesis of peptides of significant functional complexity. Kitas et al. [104] did not observe differences in reactivity for phosphoramidites d, i-k (Table 2), but the use of this type of... 

Dealkylation of Phosphonate Diethyl Ester for the Preparation of 4-Phosphonomethylphenylalanine-Containing Peptides... 

Another motivation to use phosphorus-containing peptides is related to their good structural analogy with what is called the substrate structure in the transition-state. As shown in Fig. 3, three possibilities can be envisaged and have been explored to develop potent inhibitors. Phosphonamide peptides seem the most obvious choice, as the analogy is almost perfect [11, 12]. If such compounds have been proved to yield potent inhibitors towards some zinc-metalloproteases, the limited stability of the P-N bond through hydrolysis has prevented further use of this chemistry [13-15]. Phosphonates have been reported to yield one of the most potent inhibitor ever reported for carboxypeptidase A (Ki in the fM range) [13]. However, when tested with endoproteases, phosphonates turned out to be less potent [15]. 

Dilferent, water-soluble, aryl-phosphonates (471) with oligoethylene glycol substituents were synthesised and reacted with unprotected azido-containing peptides and proteins (472) in aqueous systems, at room temperature, in high conversions via the Staudinger-phosphonate reaction to give amidophosphonates (473) (Scheme 117). ... 

Other interesting examples of proteases that exhibit promiscuous behavior are proline dipeptidase from Alteromonas sp. JD6.5, whose original activity is to cleave a dipeptide bond with a prolyl residue at the carboxy terminus [121, 122] and aminopeptidase P (AMPP) from E. coli, which is a prohne-specific peptidase that catalyzes the hydrolysis of N-terminal peptide bonds containing a proline residue [123, 124]. Both enzymes exhibit phosphotriesterase activity. This means that they are capable of catalyzing the reaction that does not exist in nature. It is of particular importance, since they can hydrolyze unnatural substrates - triesters of phosphoric acid and diesters of phosphonic acids - such as organophosphorus pesticides or organophosphoms warfare agents (Scheme 5.25) [125]. 

For the synthesis of simple peptides in which the phosphorus-containing amino acid analogue is at the C-terminal end of the peptide, acid-catalyzed cleavage of the diester has been used to produce the phosphonic diacid.153,6X1 However, the strong acid needed to effect this transformation makes the strategy unattractive for more complex molecules and it has largely been superceded by the use of bromotrimethylsilane (see Section 10.10.3.2.1). 

A sample of Z-(4-AmPhg)p(OPh)2 (1.8 g, 3.5 mmol) (or a longer peptidyl phosphonate) was dissolved in MeOH (or EtOH) (150 mL) containing ca. 2M HC1 (several mL of 4M HC1 soln in dioxane, HBr/ AcOH can also be used) and a 5% Pd/C catalyst was added. The soln was stirred under H2 until one equiv of hydrogen was consumed. The catalyst was removed by filtration and the solvent concentrated to dryness (for longer peptidyl phosphonates, the crude hydrochloride can be used directly for peptide synthesis). The residue was crystallized (EtOH/Et20) to give analytically pure product yield 60-80% mp 213-215 °C. 

Peptides of aminoalkanephosphonic acids (Phosphono-peptides 4,are now receiving considerable interest because some representatives of this class were found to repress,bacterial growth at very low concentration levels 1. Literature data on the synthesis of dipeptides containing aminoalkylphosphonic acids are scarce and very little information is avaiable,on blocking and deblocking of the phosphonate moiety ... 

Phosphonopeptides containing a transition state analog of the hydrolysis of the amide bond represent another attractive approach for the preparation of proteolitically stable peptides (10,30,31). In addition to increased stability, incorporation of a phosphonate moiety into the peptide sequence provides access to additional binding interactions within the transition-state conformation of the enzyme/substrate complex (13). This peptidomimetic approach is used to design very effective protease inhibitors (31-34). As in the case... 

Members of a second prominent group of mechanism-based inhibitors contain a peptide isostere, an element mimicking an intermediate formed during amide bond cleavage. Inhibitors of metalloproteases often contain a metal-chelating unit such as hydroxamate or phosphonic acids, which act as a bidentate ligand. 

An optimised solid-phase method for the generation of diverse a-amino-alkyl or -aryl phosphonates derived from peptides and polymer-assisted solution-phase parallel synthesis of dipeptide p-nitroanilides and dipeptide diphenyl phosphonates have been reported. A modular method for the construction of polypeptides containing the Phe-Arg phosphinic acid isostere has been described. A novel methodology for the solid-phase synthesis of phosphinic peptides has been developed in which the phosphorus-carbon bond was formed... 

Burke, T.R., Jr., Smyth, M.S., Nomizu, M., Otaka, A., and Roller, PP, Preparation of fluoro- and hydroxy-4-(phosphonoinclhyl)-i),L-phcnylalanine suitably protected for solid-phase synthesis of peptides containing hydrolytically stable analogues of O-phosphotyrosine, J. Org. Chem., 58, 1336, 1993. Ganzhorn, A.J., Hoflack, J., Pelton, P.D., Strasser, E, Chanal, M.-C., and Piettre, S.R., Inhibition of myoinositol monophosphatase isoforms by aromatic phosphonates, Bioorg. Med. Chem., 6, 1865, 1998. Kaboudin. B., Surface-mediated sohd-phase reactions. The preparation of acyl phosphonates by oxidation of 1-hydroxyphosphonates on the solid surface, Tetrahedron Lett., 41, 3169, 2000. Kaboudin, B., and Nazari, R., A convenient and mild procedure for the preparation of a-keto phosphonates of 1-hydroxyphosphonates under solvent-free conditions using microwave, Synth. Commun., 31, 2245, 2001. 

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