Protection peptide-mimetics

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

The second approach uses the more reactive isocyanates, which can be prepared from the corresponding primary amines by treatment with phosgene [254], Oligomers of hydrazine-derived ureas have been prepared as peptide mimetics on PEG in solution [255]. For this purpose, protected pentafluorophenyl carbazates have been used to convert support-bound hydrazines into ureas (Figure 16.25). 

The sulfonyl chlorides shown in Figure 16.27 have been used to prepare peptide mimetics on solid phase, either alone or in combination with protected a-amino acids [263-267] (see also Section 8.4). 

Another approach to a-ketoamide peptide mimetics was employed by Xu et al. [33] for the preparation of a human cytomegalovirus protease inhibitor library. In this case the oxidizable -OH group, protected as formate, belonged to the starting isocyanides. Thus, the reaction between N-acylated a-amino acids, amines, aldehydes, and isocyanides 42 afforded the a-hydroxyamides 43 in modest yields. Cleavage of the O-formyl bond was accomplished during the reaction by employing two... 

Scheme 14 General Course of the Combined Solid-Phase Peptide Synthesis Substrate Mimetic Fragment Condensation Approach Generation of the Protected Peptide Fragment by Aminolysis Using an Amino Acid Substrate Mimetic, and Irreversible Protease-Catalyzed Fragment Condensation ...

Klopfenstein and co-workers outlined a solid-phase route to the synthesis of peptide mimetics using the Petasis borono-Mannich reaction [57]. In this study, a Wang resin supported Fmoc-protected amino acid 57 (attached via an ester linkage) was first reductively aminated to give a secondary amine 58, which was then reacted with... 

Enantiopure N,N -hnked oligoureas were originally described in 1995 by Burgess and coworkers as novel peptide backbone mimetics [271, 272]. Several synthetic approaches have been reported, all of which involve sequential acylation and amine deprotection cycles using appropriately protected carbonyl synthons [83, 271, 272, 274, 286-288]. Although elongation can be performed in solution, most of the synthetic procedures are elaborated on solid supports starting from Rink s... 

Clearly, further studies will be necessary to sort out the multiple factors involved in the in vivo immune response to C. neoformans carbohydrate-mimetic peptides. Several conclusions may be drawn from the results to date. Peptides that mimic the cryptococcal capsular polysaccharide show specificity, in that each peptide binds with differing affinity to closely related mAbs [140,149]. The pattern of binding to protective and nonprotective mAbs differs between the mimetic peptides and the polysaccharide [140]. Protective efficacy is related to the location of carbohydrate epitopes recognized by these mAbs, within the polysaccharide capsule, but hkely also depends on interactions between mAbs and cellular responses [149]. Peptides have been shown to be functional, immunogenic mimics, but their protective efficacy depends on multiple factors, including the type of Abs elicited and interactions with the cellular immune system. Protective efficacy does not correlate with binding affinity to representative mAbs, but rather depends on the nature of these interactions. 

In the synthesis of peptides containing y-turn inducers and mimetics a key factor to consider is the ease of preparing and incorporating the inducing or mimetic moiety. In the examples described in Section 12.2.1.2, incorporation involves minor modification of standard peptide synthetic protocols. In the case of APhe, this component is relatively easy to prepare in a protected form that is fully compatible with standard Boc chemistry (Schemes 20 and 21, and Section 11.1). 

In addition to incorporating the 4-(2-aminoethyl)dibenzofuran-6-propanoic acid template into small peptides where a reverse turn is desired, we have also recently incorporated this template into a mini-protein called the PIN WW domain. WW domains have a three-stranded antiparallel p-sheet structure that mediates intracellular protein-protein interactions. 31 Substitution of this 3-turn mimetic into loop 1 of the PIN WW domain leads to a folded, three-stranded, antiparallel p-sheet structure with a stability indistinguishable from that of the all a-amino acid sequence. The template-incorporated PIN WW domain (11) was synthesized by an Fmoc-based solid-phase peptide synthesis strategy (Scheme 8), utilizing N-Fmoc-protected 4-(2-aminoethyl)dibenzofuran-6-propanoic acid 10. 11 The synthesis of 10, similar to that of 8, has been published.1 1 ... 

Olefination of aldehydes with a-silyl- and a-stannyl-stabilized phosphonate carbanions derived from cyclo-[L-AP4-D-Val] allow a (Z)-selective access to a,p-substituted vinyl phosphonates (343) that have been transformed into enantiomerically pure 4-alkylidene 4PA derivatives (344) (Figure 54). " Electrophilic fluorination of lithiated bis-lactim ethers derived from cyclo-[L-AP4-D Val] (345) with commercial NFSi allow direct access to a-monofluor-inated phosphonate mimetics of naturally occurring phosphoserine (346) and phosphothreonine (347), in enantiomerically pure form and suitably protected for solid-phase peptide synthesis (Figure 55). ... 

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