Peptidomimetic units

The acidic character of fluorinated alcohols, and consequently the excellent ability to donate hydrogen bonds, justifies their interest as central peptidomimetic units in inhibitors of serine and aspartyl proteases [2, p. 59], An enhancement of... 

Thus, the monofluoroalkene moiety is a non-hydrolysable isostere of the pep-tidic bond, and hence can be used as a peptidomimetic unit in the design of protease inhibitors [59,60]. This type of rigid isosteres of the peptidic bond can facilitate the cisjtrans conformational control of the fragment replaced. Because of the double bond, the bond length and angles of the peptidic bond are suitably mimicked, and the fluorine atom complements the analogy for electronic properties. This approach has been developed in the case of prolylamide fragments, in... 

Imines and (Af,(9)-acetals from fluoral are useful precursors of trifluoromethyl nitrogen-containing molecules amines, amino alcohols, amino acids, peptidomimetic units, heterocycles, and so on (Figure 2.50). These simple Af-derivatives of fluoral are easily prepared from the hydrate or the hemiacetal. Imines of fluoral react in [2 + 1 ]... 

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. 

Numerous nonproteogenic a- or jS-fluorinated amino acids and amino alcohols have been prepared as peptidomimetic units. Unfortunately, due to lack of space, they have not been included in this book. Recent reviews have been dedicated to some of these compounds. ... 

Some peptides that contain peptidomimetic units IPICF = C] have been studied. Among them, prolylamides have exhibited the most striking results. The differences in the inhibition properties between the tetrapeptides with IPICF = CJPro and those with TiCH = CJPro as peptidomimetic units are significant. The trans conformation of the amide bond of a peptide is generally considered to be more stable than the cis... 

Figure 35 Examples of models for peptide and peptidomimetic units used to build up the template library in Generate.

Stereoselective and Enantioselective Synthesis of New Fluoroalkyi Peptidomimetic Units Amino Alcohols and Isoserines... 

Alkylation of the azetidinone 26 is also efficient. The lithium enolate of 26 could be generated with the use of lithium hexamethyldisilyl amide, and various electrophiles reacted to provide the substituted azetidinones 36. During this reaction the relative configuration of CF3 and benzyloxy groups was conserved. The ratio of the trans minor isomer was about only 0-20 %. This stereochemistry results from the a-entrance of the electrophile by the less congested face, and is only slightly dependent on the bulkiness of the electrophile. These new substituted p-lactams 36 offer an access to new fluoroalkyl analogues of peptidomimetic units, and of taxotere side chain. 

This study provides a stereoselective route to syn and anti P-amino trifluoromethyl alcohols and to syn and anti trifluoromethyl isoserines. These new preparations allow an access to enantiomerically pure fluoroalkyl amino alcohols which can be used as peptidomimetic units for the design of fluoroalkyl analogues of bioactive compounds. These methods can be extended to different patterns of substitution (Rf and R). 

The central unit of these peptidomimetics imitates a /1-turn and brings the NH2-terminus of the cysteine analogue and the CO OH terminus of the methionine in spatial proximity these can then complex the Zn2+ ion which is essential for activity of the FTase [26]. The free acid 7 inhibits the enzyme with an IC50 value of 1 nmol/1, whilst in intact cells the methyl ester 8, despite its weaker in vitro activity, is significantly more potent because it can penetrate the plasma membrane better due to its lower polarity. This property can be used to convert the morphology of H-Ras-transformed cells back to the normal form and to inhibit growth of these cells, whereas the substance shows no effect on Src-transformed and untransformed rat fibroblasts. The inhibitor therefore acts selectively on transformed cells and does not influence growth of normal cells. This result is noteworthy because farnesylation of the wild type H-Ras protein... 

Recently, the same ai,p3 target has been addressed with lipidic nanoparticles containing a huge number of Gd-chelated units (94,400 Gd/particle characterized by ri = 19.1 s mM (per Gd) = 1,800,000 per particle). One of the lipidic components is covalently bound to the ot p3 - integrin peptidomimetic antagonist (168). 

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. 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules with biological relevance. The ability to prepare haloarenes selectively by an ortho-metallation halogenation sequence allows for the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metallation to form aryl halides that were subsequently reacted with anilines to prepare diarylamines (Eq. 34)) [156]. Frost and Mendon a have reported an iterative strategy to prepare (by palladium-catalyzed chemistry) amides and sulfonamides that may act as peptidomimetics. Diarylamine units are constructed using the DPPF-ligated palladium catalysts, and the products are then acylated or sulfo-nated with 4-bromo benzoyl or arylsulfonyl chlorides [157]. 

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