Surrogates, amino acid

Kaldor SW, Dressman BA, Hammond M, Appelt K, Burgess JA, Lubbehausen PP, Muesing MA, Hatch SD, Wiskerchen MA, Baxter AJ. Isophthalic acid derivatives amino acid surrogates for the inhibition of HIV-1 protease. Bioor. Med. Chem. Lett. 1995 5 721-726. 

Valiyaveetil FI et al (2004) Glycine as a D-amino acid surrogate in the K+-selectivity filter. Proc Nat Acad Sci USA 101 17045-17049... 

These amino acid surrogates have side chains locked cis or trcms to the amino functionality and the cyclopropane ring also restricts rotations about the N-Ca and Ca-CO bonds... 

Valiyaveetil FI, Sekedat M, Mackinnon R, Muir TW. Glycine as a d-amino acid surrogate in the k(- -)-selectivity filter. Proc. Natl. Acad. Sci. U. S. A. 2004 101 17045-17049. 

The secondary amino acid Pro is generally considered an a-helix breaker. Secondary amino acid surrogates, which also mimic the effect of Pro, can potentially disrupt secondary structure formation. They are attractive in SPPS, if the modification which transiently made them secondary amino acid can be removed after peptide chain assembly. This has been used in two synthetic methods. 

C-H activation a to nitrogen generates f3-amino acid derivatives (Figure 5). Therefore, the reaction can be considered to be a surrogate of the Mannich reaction. 

As stated above, we define pseudopeptides as compounds having a modified peptide backbone, namely with at least one peptide bond replaced by a bioisosteric surrogate (summarized in Table 6.7) [139][181][234], Such surrogate groups are nonhydrolyzable by nature, or hydrolyzable only under severe conditions in the case of the S02-NH bond. In the vast majority of published pseudopeptides, only one or a very few peptide bonds had been replaced and most monomeric units are amino acids, meaning that such pseudopeptides do qualify as peptides. 

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. 

Ojima and coworkers have developed a similar approach to the synthesis of piperidine and related ring systems, which they describe as cyclohydrocarbonylation. In this approach, carbamate-protected allylglydnes (for example, 32) are subjected to rho-dium(I)-catalyzed hydroformylation in an alcohol solvent (Scheme 5.13) [17]. 6-Alkoxy-pipecolates 33 are isolated in good yield and were shown to be amenable to further stereoselective transformations. This methodology has recently been expanded to include fully intramolecular variants that can form two rings in a single reaction. Thus, alkenes 34 are subjected to the cyclohydrocarbonylation conditions to provide azabicy-clo[4.4.0]aUcane amino acids 35 which can serve as conformationaUy restricted dipeptide surrogates and /9-turn mimetics [18]. 

A.F. Spatola, Peptide backbone modifications A structure-activity analysis of peptides containing amide bond surrogates, conformational constraints, and related backbone replacements, in B. Weinstein(Ed.), Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, Marcel Dekker, New York, 1983, pp. 267-357. 

The Rh-BIPHEPHOS-catalyzed cyclohydrocarbonylation has also been successfully applied to the rapid synthesis of a variety of l-azabicyclo[X.Y.O]alkane amino acids, which serve as conformationally restricted dipeptide surrogates for enzyme inhibitors and receptor antagonists, directly from dehydrodipeptide substrates (Scheme Reaction... 

The retro-peptide bond is a true isosteric peptide bond surrogate and as such may offer an important tool to study topics such as the functional role of the peptide backbone in peptide hormone-receptor interactions, and modulation of metabolic stability and bioavailability. Partially modified retro-inverso-peptides (PMRI-peptides) (e.g., 2-4, 7 Scheme 1) result from a retro-inverso transformation of one or several peptide bonds in an amino- and carboxy-free peptide (e.g., 5 Scheme 1). Evidently, partial or exhaustive retro-inverso transformations result in the introduction of two non-amino acid residues into the... 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

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