Peptide aldehyde

I.V-CartMnykfrimidazole 2 an activating reagent torcartx)xyHc acids in tormation of esters, amides, peptides, aldehydes and ketones via inMazolldes 3. 

More than 50 endogenous and exogenous inhibitors of the calpains have been described as either transition-state reversible or irreversible inhibitors. The first transition-state inhibitors were the peptide aldehydes (e.g., leupeptin). Using this compound, new ones were synthesized that exhibited improved membrane permeability and calpain specificity (e.g., calpeptin). Other groups of inhibitors have since been discovered a-dicarbonyls (originally developed as serine protease inhibitors), nonpeptide quinolinecarboxamides,... 

Another PDF inhibitor series derived from comparisons with known metalloprotease inhibitor classes has been reported by Merck [68]. Their study investigated a small set of peptide aldehyde inhibitors, postulating that the aldehyde might bind to the metal centre in the form of a hydrate,... 

Polar polyoxyethylene-polyoxypropylene (POEPOP) resin, deriva-tized with a 4-hydroxymethyl phenoxy linker, was used as a solid support for lanthanide triflate-catalyzed Mukaiyama-type solid-phase aldol reactions.282 The use of an aqueous solvent was found to be crucial. The reactions on an N-terminal peptide aldehyde substrate proceeded in very high yields. 

Direct thrombin inhibitors such as hirudin, Hirulog, the peptide aldehyde efegatran, and peptidomimetic compound argatroban have undergone clinical trials. Their application in the prevention and treatment of deep vein thrombosis contin-... 

Serine and threonine Halomethyl ketones, peptidic aldehydes... 

The fitting was not successful for the peptide-aldehyde inhibited form of the SGPA enzyme underlining the alignment difference between the active site residues His57 and Asp 102 between the two forms of this enzyme (cf. Ref. 118). 

E. Dufour, A. C. Storer, R. Menard, Peptide Aldehydes and Nitriles as Transition State Analog Inhibitors of Cysteine Proteases , Biochemistry 1995, 34, 9136 - 9143. 

Proteasome inhibitors have been instrumental in identifying numerous protein substrates and in elucidating the importance of the proteasome/ubiquitin pathway in many biological processes. Initially, non-specific cell-penetrating peptide aldehydes were used for this purpose. More recently, it became possible to synthesize compounds with increased potency and selectivity (Adams et al. 1998 Elofsson et al. 1999). Furthermore, based on the crystal structure of the yeast and bovine liver CP (Groll et al. 1997 Unno et al. 2002), molecular modeling can now be used to engineer improved inhibitors. 

T. L. Bullock, K. Breddam, S. J. Remington, Peptide aldehyde complexes with wheat serine carboxypeptidase II, implications for the catalytic mechanism and substrate specificity. /. Mol. Biol. 1996, 255, 714-725. 

Leupeptin is a slow, tight-binding inhibitor of trypsin. Some peptide aldehydes are potent, reversible inhibitors of cysteine proteases forming hemith-ioacetals with the active site cysteine.1 Similarly, peptide nitriles form thioimidate adducts.h... 

Preparation of a Am-Urethane Protected -Amino or Peptide Aldehyde... 

Scheme 9 Solid-Phase Synthesis of an a-Amino or Peptide Aldehyde by Reduction of the Corresponding Weinreb Amide LinkerN...

Preparation of a N -Protected a-Amino (and Peptide) Aldehyde on Solid Support via the Weinreb Amide Linker General Procedure 461... 

Interest in linkers for carbonyl compounds has only slowly emerged in recent years. The main driving force for the development of such linkers was the need for methods to prepare peptide aldehydes and related compounds (e.g. peptide trifluoromethyl ketones), which can be highly specific and valuable enzyme inhibitors [700,701], and are potentially useful for the treatment of various diseases. 

The optical purity of peptide aldehydes can be determined by conventional methods such as the transformation of the aldehyde to the corresponding alcohol and determination of the optical purity of the alcohol by optical rotation. 11 Alternatively, the enantiomeric purity can be determined via NMR spectroscopy of the semicarbazone derivative or HPLC using chiral columns. 1718 ... 

The first synthesis of peptide aldehydes involved amino acid residues with no side-chain functional groups. Subsequently, peptide aldehydes with a number of side-chain functional groups have been synthesized. Protecting groups utilized include Arg(N02), Lys(Z), Asp(OCy), Asp(OtBu), Glu(OtBu), Ser(Z), Thr(tBu), and Cys(Z). 311 1319 20 It should be noted that many unprotected side-chain functional groups will react with the aldehyde functional group and this is discussed in Section 15.1.1.1. 3,5,11,21 ... 

Scheme 1 Reduction of Peptide Esters to Peptide Aldehydes with Diisobutylaluminum Hydride...

The mechanism of diisobutylaluminum hydride reduction involves formation of a six-membered transition state with aluminum complexed to the carbonyl of the ester group, which is required for the delivery of the hydride from the electrophilic aluminum hydride to the carbonyl group. The alkoxy moiety is then displaced during workup resulting in the desired peptide aldehyde. This mechanism accounts for the fact that the reduction stops after the conversion of the ester into the aldehyde. 23 ... 

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

Amino acid and peptide aldehydes with one to three residues have been prepared successfully using diisobutylaluminum hydride. Z-Protected amino aldehydes such as Z-Leu-H, Z-Phe-H, Z-Cys(Bzl)-H, Z-Pro-H have been synthesized with little or no racemization (Table l). 5 The diisobutylaluminum hydride reduction can be used with both peptide esters and Z amino acid esters. However, the Boc protecting group is less stable when refluxed with diisobutylaluminum hydride, thus resulting in its loss while reducing Boc-Ala-OMe or Boc-Ser(OBzl)-OMe. 13 ... 

Peptide aldehydes are fairly reactive and usually exist in solution partially as hydrates Xaa[CH(OH)2] (e.g., 3), which are identified using 13C NMR spectroscopy. 3 3" With amino acids containing nucleophilic side chains, cyclized forms predominate (Scheme 2). Argininal analogues such as Z-Leu-Phe-Arg-H have been shown to exist primarily as the carbinol amine 4 with no spectroscopic evidence for an iminium structure. Lysinal derivatives such as Z-Leu-Phe-Lys-H exist both as a cyclic carbinol amine 5 and as an iminium ion 6 as shown by 3H and 13C NMR spectra. The C-terminal ornithinal analogue Z-Leu-Phe-Orn-H exists primarily as the carbinol amine form 7 and the cyclic iminium form 8 as characterized by the 13C NMR spectra. 3,21 In general, the existence of carbinol and iminium cyclized forms does not preclude the existence of the free or hydrated aldehydes under aqueous conditions. 

The extent of racemization of peptide aldehydes exposed to silica gel has been determined as a function of time (Table 3).b0 The amount of racemization increases in the order Z-Cys(Bzl)-H > Z-Phe-H > Z-Leu-H > Z-Arg(N02)-HJ5 The unusually small amount of racemization observed with Z-Arg(N02)-H is probably due to its cyclic carbinol amine structure, which prevents racemization through a keto-enol mechanism. More racemization is seen in aldehydes possessing side chains such as Z-Cys(Bzl)-H that favor enolsJ15 ... 

Protection of peptide aldehydes as semicarbazones serves two purposes (1) it reduces or eliminates racemization during chromatographic separation, and (2) the semicarbazone protects the aldehyde functional group during subsequent peptide coupling reactions. Crude aldehydes can be immediately reacted with semicarbazide hydrochloride to give the corresponding semicarbazones. The semicarbazones are purified on a silica gel column and are subsequently deprotected with 37% formaldehyde/HCl. To determine the optical purity, the aldehydes are immediately reduced with sodium borohydride followed by determination of the optical rotation of the alcohol (Table 3).[5]... 

Semicarbazones of peptide aldehydes are stable to hydrogenolysis and various coupling procedures (azide and mixed anhydride). Deprotection of the Z-protected amino acid semicarbazones, such as Z-Phe-H semicarbazone, by catalytic dehydrogenation gives the deprotected derivatives in good yields,these can be coupled to peptide azides or peptide acids using the mixed anhydride procedure. The semicarbazone is readily deprotected with 37% formaldehyde/HCl to give the peptide aldehyde. 

Peptide aldehydes have also been prepared successfully by direct reduction of Weinreb amides. Peptide linkages were stable during the reduction of dipeptide /V-methoxy-/V-methylamides. For example, the dipeptides Boc-Phe-Leu-H and Z-Tyr-Val-H were prepared in 96-98% yield (Table 6)J351... 

Table 6 Synthesis of Peptide Aldehydes R -Xaa Xaa -H by Reduction of Weinreb Amides R1-Xaa2-Xaa1-N(Me)OMe with Lithium Aluminum Hydride135 ...

Peptide aldehydes 1 can be synthesized effectively by the oxidation of peptide alcohols 15, which are readily available without racemization by reduction of peptide esters 9 with sodium borohydride-lithium chloride (Scheme 5). The peptide alcohols 15 can be readily oxidized to afford enantiomerically pure aldehydes using Parikh-Doering or Dess-Martin reagents. This route is less popular than the previously described reductive methods due to (1) the sensitivity of the aldehydes to further oxidation, (2) racemization under the reaction conditions, and (3) instability of the products under the reaction conditions. 

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