Bicyclic peptidomimetic

J )-aminoboronic esters, which are coupled to the pentapeptides or to the bicyclic peptidomimetics (Scheme 2.4) [152]. 

Table HI. Bicyclic peptidomimetics using chiral amines...

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

A similar scaffold for the preparation of peptidomimetics was prepared by Mitsunobu cyclization of the molecule coming from the coupling of 4-benzylprolinol and iV-nosyl(o-nitrobenzensulfonyl) tryptophan 316 (Scheme 41). A Mitsunobu cyclization occurred easily due to the acidity of the NH of the nosyl group that could be further selectively deprotected under very mild conditions. The so-formed bicyclic amine 317 can be further coupled with different amino acids to give compounds 318, employed in the search of a new somatostatin pharmacophore <2005BML4033>. 

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. 

Slomczynska, U., Chalmers, D.K., CORNILLE, F., Smythe, M.L., Beusen, D.D., Moeller, K.D., Marshall, G.R. Electrochemical cyclization of dipeptides to form novel bicyclic, reverse-turn peptidomimetics. 2. Synthesis and conformational analysis of 6,5-bicyclic systems./. Org. Chem. 1996, 63(4), 1198-1204. 

The hexahydropyrazinones 179 were subjected to further peptide coupling with various AT-protected amino acids, deprotection and repeated cyclization to give bicyclic dipeptides with a spirocyclopropaneoctahydropyrazinopyrazine skeleton of type 182 (Scheme 54). Compounds of the types 182 and 179 represent potentially useful classes of geometrically defined peptidomimetics. For example, the skeleton of 179 has been found in the hydrolysis products of the naturally occurring lysomarasmine [90]. 

In the following discussion a selection of optimized procedures is presented for the synthesis on solid support of homodetic monocyclic and bicyclic as well as mixed homodetic/ heterodetic bicyclic peptides that contain at least one lactam ring, whereas heterodetic cyclic peptides containing other than amide bonds or peptidomimetics are not discussed here because of their unlimited diversity. 

Scheme 48 Bicyclic p-Turn Peptidomimetic and Its Incorporation into a Cyclic Peptide,165l...

The broad-spectrum peptidomimetic lAP family inhibitors were also recently developed (107). Designed based on (7, 5)-bicyclic scaffold, these SMAC-mimetics were found to antagonize the protein interactions that involve XIAP, melanoma... 

Another type III peptidomimetic inhibitor was derived from the crystal structure of a bicyclic [3.1.3] inhibitor (170) complexed to thrombin (97) (Fig. 15.41). The X-ray structure revealed that one of the carbonyls was oriented towards the hydrophobic P-pocket (S2). The desolvation necessary to place a carbonyl in a hydrophobic pocket is unfavorable and various alkyl groups were used as possible replacements. This led to the potent (iCj = 13 nM) and selective (>760 for thrombin over tiypsin) inhibitor (98). 

Hanessian, S., and Auzzas, L. (2008) The practice of ring constraint in peptidomimetics using bicyclic and polycyclic amino acids. Acc. Chem. Res. 41, 1241-1251. 

Fig. 4 Structure of peptide and peptidomimetics (a) Structure of AVPIAQKSE bound to the BIR domain of ML-IAP, only the four N-terminal residues of the peptide are ordered in the structure (b) Structure of [7,5]-bicyclic-y-thioproline 8 also bound to the BIR domain of ML-IAP. Note the conservation of interactions with between the peptide and the protein...

Diazabicyclo[4.3.0]nonene-based peptidomimetics with a quaternary chiral centre are prepared via intramolecular condensation of A -aminopropyl-y-lactam [27]. Reductive amination of oxazolidinone aldehydes with A -monoprotected propylenediamine give A -phthalimidopropyl lactams however, trials of cyclization to bicyclic amidines after deprotection under dehydration conditions are unsuccessful. To solve this problem, the phthalimides are converted to thiolactams with Lawesson reagent. Deprotection followed by treatment with mercury (11) chloride (HgCl2) yields desired cyclic amidines (Scheme 3.14). 

On the other hand, reaction of D-glucorono-3,6-lactone 55 with L-cysteine ester 56 gave stereoselectively the bicyclic thiazolidine lactam 57, a precursor for polyol peptidomimetics [90,91]. The thiazoUdine 58 was found to be... 

The dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG) selectively enhances the binding of agonists to dopamine receptors in the mammalian central nervous system. Johnson and co-workers at the University of Minnesota and McMaster University have prepared bicyclic 5,5- and 6,5-thiazolidine lactam peptidomimetics (82, 83) in an attempt to elucidate the bioactive conformations of PLG. 

M. J. Genin and R. L. Johnson,/. Am. Chem. Soc., 114, 8778 (1992). Design, Synthesis and Conformational Analysis of a Novel Spiro-Bicyclic System as a Type II B-Turn Peptidomimetic. 

The described peptidomimetics with an unprecedented structural flexibility, allows one to combinatorially address up to four points of diversity for the mono- or bicyclic systems, including also the control of all chiral centers. 

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