Peptidomimetics method

High throughput methods have increased our capacity for appropriate candidate compounds selection and also for developing libraries of novel compounds from which such candidates can be selected. Chapter 7 discusses the use of solid-phase synthesis for the high throughput production of peptides and other small molecules. In addition, as discussed in Chapter 6 on peptidomimetics, the swift production of novel leads holds considerable promise for future discovery of novel therapeutic agents. 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Goodman, M., Felix, A., Moroder, M and Toniolo, C. (Eds.) (2002). Houben-Weyl Methods of Organic Chemistry, Vol E22, Synthesis of Peptides and peptidomimetics. Vol E22a, The synthesis of peptides, 901pp. Goerg Thieme Verlag Methods with experimental procedures. 

Nisin, because of its continued use as a preservative for more than 30 years 661 became an obvious target for a total synthesis 13 To date, it remains the only naturally occurring lanthionine peptide for which this feat has been achieved. In contrast to the lanthionine peptide syntheses of most other approaches already discussed, the total synthesis of nisin is based on a solution-synthesis strategy. Whilst, the total synthesis of the pentacyclic, 34-residue peptide nisin also demonstrated that such syntheses are not a commercially viable option for large amounts of lantibiotics, they have opened the way to useful synthetic methods for the synthesis of novel conformationally constrained peptides and peptidomimetic compounds. 

P61 Kazmierski, W. M., Methods in Molecular Medicine Peptidomimetic Protocols, Humana Totowa, NJ, (1999). 

Some of the versions of the mixed anhydride technique discussed may involve components other than a-hydroxy acids. Therefore, the resultant products cannot be considered as main-chain modified peptidomimetics. However, on many grounds these methods are of general importance in depsipeptide synthesis. For example the classical peptide reagent isobutyl chloroformate appears to be suitable for ester bond formation through the corresponding mixed anhydride with Boc- or Z-protected amino acids and the Thr (3-hydroxy group in the synthesis of a number of natural peptide lactones.145 7 ... 

I Henninger, T. C. Wipf, P., In Methods in Molecular Medicine Peptidomimetics, Kaz-mierski, W. M., Ed. Humana Press Totowa,... 

Scheme 2 Methods for Constructing Ureine Peptides and Peptidomimetics...

Molecular modeling calculations using ab initio methods (MP2/6-31+G ) predict that spiro-(3-lactam of type M adopt a (3-tum secondary structure [50] which is very close to the ideal type-III (3-tums. Thus, these spiro-(3-lactams are the important members of the core for the preparation of different types of peptidomimetics using well-established chemistry. They combine the structural features required for inducing (3-tum motif. 

The introduction of conformational restrictions into flexible active molecules is a well-known strategy for trying to increase their potency and/or selectivity toward their biological targets.1 Several methods have been used for constraining flexible molecules. Cyclic derivatives of hnear peptides or peptidomimetics can thus be prepared by reactions involving side-chain... 

It has been shown also that both thiocarbamoylimidazoles 147 and 148 can react with sodium azide. These compounds were successfully used to prepare heterocycle-peptide conjugates as peptidomimetics. A-Terminal aminothiatriazole modified amino acids have been synthesized using two methods (Scheme 35). To prepare monosubstituted aminothiatriazoles 151 the amino acid derivatives were converted into the thiocarbamoyl imidazoles of type 147 that can react with azide ion to form the thiatriazole ring. On the other hand, for the synthesis of disubstituted amino acid derivatives of 1,2,3,4-thiatriazoles 153 and 155 the activation of the thiocarbonyl group via a salt of type 148 was required. The reaction conditions and the yields of thiatriazoles 151, 153, and 154 prepared by this approach are shown in Scheme 35. 

Resolutions of racemic mixtures are by far the most frequent applications of biocatalysts in the pharmaceutical industry. Repic et al., of the process research and development group at Novartis, recently published work to develop a method for the resolution of racemic (3-amino acid esters, an important class of intermediates for the preparation of peptidomimetics [21]. The Novartis group used Chiro-CLEC -EC [22] in 2% aqueous toluene to selectively acylate several different 3-amino esters (Fig. 4). The authors were able to isolate the desired (S) isomer of the amino esters in >95% ee in a simple one-step reaction and described it as a method which could be amenable for large-scale preparation. 

The chapter by Kiely reviews the preparation of libraries as mixtures from 1995 to the present. The important areas which are reviewed are methods of preparation, means of identifying active compounds from the mixtures, and why one might wish to prepare mixtures. The chapter also includes the preparation of mixtures of non-peptide molecules, as well as peptidomimetic molecules, and even a few examples of peptides. Examples are presented where mixture synthesis and screening have been effective in identifying interesting biological leads. 

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