Y-tums

U-pin is most comparable to a six-ring hairpin polyamide, likely due to a loss of two hydrogen bond donors upon removal of the y-turn element. Thus, the dimeric Py-lm U-turn element may be thought of as a C,G-specific replacement for the y-tum (Fig. 3.4). In combination with removal of the /9-Ala tail (see below), H-pin and U-pin polyamides could potentially bind purely G,C sites, a sequence type that has been difficult to target with other polyamide motifs. 

Recently, the cyclopropanation of (Z)-4-benzyIidene-2-phenyl-5(4//)-oxazolone 621 with phenyldiazomethane was reported to give the spirocyclopropane, rac- 21 in very high yield. Subsequent ring opening and hydrolysis of rac- 21 generated frani-l-amino-2,3-diphenyl-l-cyclopropanecarboxylic acid, rac-828 (cadiPhe) (Scheme 7.256). This new, constrained phenylalanine analogue induces a y-tum in the sohd state when incorporated into model dipeptides. The enantiomers of the Al-Boc (Boc = tert-butyloxycarbonyl) methyl ester of 828 have been resolved by HPLC. 

Volume E 22 12.2 Synthesis of Peptides Incorporating y-Tum Inducers and Mimetics... 

For L-amino acids y-turns can be divided into two subgroups, the so-called inverse (or equatorial) (,ap values generally between —95 to —70°, 45 to 75°) and classic (or axial) ([Pg.741]

Of the two, classic ones are far less common however, those that do exist are frequently found at the loop end of 3-hairpinsJ81 Inverse y-tums generally do not lead to peptide chain reversal and are frequently situated at either the end of a-helices or within strands of p-sheets or adjacent to certain loop motifs. 91 They are generally well conserved during evolution and some are found at key positions within proteins. 

It has been suggested that y-turns are present in the solution structures of several peptides, and furthermore implicated in their bioactive conformations 101 including brady-kinin, 111 substance P,1121 cyclic somatostatin analogues, 131 cyclolinopeptide, 141 and the 6-opioid receptor bound conformation of enkephalin. 151 Yet, despite the fact that y-tums are frequently hypothesized to represent important features of secondary structure 161 based upon computational,1171 IR absorption,1181 NMR spectroscopic,119 201 and X-ray diffraction crystallographic determinations,1211 verification of the role of this predicted secondary structural element remains a difficult, but nonetheless critical step. 

Reetz et alJ33 described the stereoselective synthesis of partially protected a-hydroxy-y-amino acids 8 (Scheme 6) as potential pseudo-y-tum mimetics. X-ray diffraction structure analysis as well as NMR studies in CDC13 showed that these compounds display a pseu-docyclic eight-membered ring arising from an intramolecular H-bond between the amide carbonyl (i -1) and the alcohol hydroxy group (i). However, the ability of such a H-bond to induce or stabilize a pseudo-y-turn structure in an aqueous environment is doubtful. 

Scheme 7 y-Tum and Retro-amide y-Tum Mimetic Containing RGD Analogues 34,35,37 ... 

A six-membered lactam ring 17 (Scheme 11) was incorporated into bradykinin in which a y-turn formed between residues 6-8 had been hypothesized to be one potential bioactive conformation. 10 One of the diastereomers was found to show moderate (micromolar) affinity for the bradykinin receptor despite lacking the proper side chains of Ser6 and Pro7. The result tends to support the presence of a reverse turn (either a y-tum or, more probably, a p-turn) at this site. 

Scheme 19 Synthesis of a Bradykinin Analogue Incorporating a y-Tum Mimetic110 1...

Cyclic 11-,14-, 17-, 20-, and 23-membered rings stabilize p-tums, y-tums, /3-turas//3-sheets. Stabilize a-helices, jS-tums. 

Conformational restriction can be introduced into flexible peptides by a variety of methods. For example, Marshall et al. introduced a-methyl amino acid substituents into peptides as a way to decrease the conformational space available to the resulting peptide. Freidinger et al. developed a cyclic lactam moiety (23.31) that stabilized p- and y-tum structures and applied this to LH-RH (e.g. (23.32)) to show that a p-tura about residues 6-7 was compatible with activity." Conformational restriction has been applied to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett" synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin-converting enzyme (ACE) inhibitors enalapril (2333) and enalaprilat (23.34) (Fig. 23.6) in order to characterize torsion angles in the bioactive conformation. Analog (23.35) was used to constrain... 

While this monocyclic reverse-turn template clearly mimics the backbone conformation and side-chain presentations of p- and "y-tums quite well, one concern with such a large macrocycle is that the relatively flexible peptide backbone conformations are strongly influenced by the side-chain-side-chain interactions, as investigated by NMR solution structure (Fig. 29.11). ° We therefore needed a new type of turn mimetic bearing a constrained and rigid skeleton which could potentially enhance binding and/or improve bioavailability. Based on the conformational analyses of several heterobicyclic systems, we envisioned... 

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