Peptidomimetic synthetic

Synthesis of unusual amino acids, peptidomimetics, synthetic enzymes, and new drugs containing (5-lactam rings as an integral part of their structure, has currently renewed interest worldwide in this four-membered heterocycle [52-54]. Furthermore, the appropriately substituted and configured(5-lactam frameworks now constitute effective tools for the incorporation of a wide variety of both (5- and a-amino acids in short peptide segments of various biologically active molecules. 

Synthetic heterocyclic and modified amino acid derivatives have been grouped in a class of thrombin inhibitors called peptidomimetics. An example of such a compound is argatroban, with a molecular mass of 532 Da. It blocks thrombin s active catalytic site by binding to the adjacent apolar binding site. This selective reversible inhibitor of thrombin has a K of 19 nM and blocks thrombin s role in coagulation and fibrinolysis (62). 

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. 

The numerous applications of fluorinated amino acids in medicinal chemistry and in enzymology have induced a large number of studies dedicated to their synthesis. Synthetic chemists have provided protein biologists and chemists with an incredible range of fluorinated amino acids. Since this work has been covered in the literamre, we only review some representative examples of proteogenic fluorinated amino acid analogues, with special focus on the synthetic aspects proper to fluorine chemistry. The numerous fluorinated peptidomimetic units (e.g., amino alcohols) are not included in this chapter. 

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. 

Peptidomimetics is an active branch of patterned synthesis. A notable family of tumor-avid peptides was derived from synthesis patterned on neurotensin, a peptide constituted of 13-amino acids. These synthetic peptides bind to the NT receptors expressed by many forms of cancer, which may serve to map the tumor, delivering radionuclides in situ (Waibel 2000). Molecules that, like the peptides, are constituted of repetitive blocks, are much simpler to synthesize than those composed of non-repetitive units. Given the powerful bioactivity, and improved stability on systemic administration, synthetic peptides may become rewarding it as it has been estimated, one in two men, and one in three women, will get cancer in their lifetime. 

Low-molecular-weight antagonists are attractive due to their low cost and bioavailability. Available literature indicates that many laboratories are attempting to create immunomodulators of small synthetic molecules, peptidomimetics, bacterial cell-wall components, macrocycles, corticosteriods, and others [74]. 

Given the extensive biology associated with peptides, it is not surprising that considerable effort has been devoted to the synthesis of peptidomimetics to overcome the unfavorable properties and therapeutic deficiencies of peptides. In particular, since the advent of solid-phase synthesis and, more recently, combinatorial chemistry, interest in peptido-mimetic design and preparation has exploded. In theory, the peptide chemist is only limited by their imagination in the novel modifications that can be tailored for synthetic peptide analogues. 

The concept of tweezer-like two-armed molecules was used to construct synthetic receptor molecules based on methylene sulfonamide peptidomimetics.11291 When screened for binding against an encoded tripeptide library, one of the synthetic receptors demonstrated a remarkable binding selectivity 11291 the synthetic receptor affinity could be further increased by varying the hinge part of the peptidomimetic molecule.11301... 

Sections 12.1 and 12.2 discuss the synthetic aspects of peptidomimetics of turn elements ((3- and y-turns, respectively)l6-151 Peptides incorporating helix and (3-sheet inducers and mimetics110 15-21 are covered in Sections 12.3 and 12.4, respectively. 

Scheme 19 Synthetic Scheme for the Preparation of 3-Turn Peptidomimetics[92-931...

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