Reduced amide bond

The methyleneamino(hydroxy) or i >[CH2-N(OH)] link 2, which may be also called an N-hydroxy reduced amide bond, was introduced by Grundke et aL in 1987.W Compound 13 can be obtained in good yield by reduction of the homologous (nitrono) peptide 12 (Scheme 2). Alternatively, Urban et aI.15 have prepared the (IV-hydroxy reduced amide) peptide 15, a potent HIV protease inhibitor, by direct oxidation of the amine nitrogen in the homologous reduced peptide 14, obtained by classical reductive amination (Scheme 3). 

Table 2. Inhibition of FTase by Tetrapeptides Incorporating Reduced Amide Bonds...

Reduced Amide Bonds and Other Transition-State Analogs... 

Because of the wide occurrence of proteolytic hormones involved in various diseases, peptidomimetic inhibitors based on incorporation of a transition-state analog with a tetrahedral carbon to replace the carbonyl carbon of the sessile amide bond have been a dominant strategy. The simplest analog replaces the amide with a methylene amine, or a reduced amide bond. 

Modified peptides containing reduced amide bonds, i. e. compounds L-731,735 and L-731,734, were designed by the Merck groups [7] (Fig. 1), and have shown to be potent inhibitors of partially purified FPTase, the homoserine compound being the more active inhibitor in vitro. Subsequent inhibitors include L-739,749 and L-739,750 [8] and even trancated versions of the C-terminal tetrapeptide CAAX motif were prepared which do not have a C-terminal carboxyl... 

In the past 15 years, peptide analogues containing the reduced amide bond i/[Pg.650]

C. Procedure for the Synthesis of the Reduced Amide Bond on Solid Support [28,76]... 

Cross-hnked polyacrylamides are a group of hydrophihc solid supports introduced primarily for preparation of biopolymers (Fig. 4). Unhke PS resins, polyacrylamides have excellent swelling capacity in both protic (water, alcohols) and aprotic (dichloromethane, dimethylformamide) solvents [88]. These beads are stable towards bases, acids, and weak reducing and oxidizing agents [89]. Predictably, conditions under which amide bonds are cleaved (i.e., sodium in liquid ammonia) [90] lead to rapid decomposition of the polymer. 

Thus, the tendency is that in the absence of any adjacent substituent on either side of an amide bond, the 12-membered turn is favored, the 10-membered being formed when the amide bond is flanked by substituted carbons. The reduced 12/ 10-hehx population or rearrangement to the 3i4-hehx observed upon N-terminal deprotection of mixed /9-peptides can be explained in terms of unfavorable... 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

With this information in hand, initial attempts to generate BACE inhibitors used the peptidic Swedish variant substrate as a starting point and substituted the scissile amide bond with a statine. For example, Sinha et al. (1999) synthesized a P10-P4 1 Swedish variant peptide with a statine moiety in place of the Pl-Pl scissile bond and showed that this peptidomimetic displayed an IC50 of 40 pM for inhibition of BACE. Optimization of this inhibitor was then performed by systematic replacement of amino acid side chains. Replacement of the PE Asp residue by Val reduced the IC50 for BACE inhibition to 30 nM this inhibitor is referred to here as Stat-Val. 

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