Conformational restriction bioactivity

Synthetic cyclic peptides are of eminent interest not only as replicates or analogues of natural products or as conformationally restricted bioactive peptides and peptide or protein fragments, but may also serve for specific purposes as listed in the following sections. 

As in the case of the five-membered proline analogues, besides pipecolic acid (6) as the six-membered homologue of proline, related aza-, oxa-, and thia-analogues are used to mimic the conformationally restricting properties of proline in the peptidomimetic design of bioactive compounds.1202 ... 

The studies discussed in the preceding sections demonstrate both the potential and the limitations associated with the use of conformationally restricted amino acids for elucidating bioactive conformations. Even... 

Conformational restriction is a very powerful method for probing the bioactive conformations of peptides. Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. For example, a simple tripeptide such as thyrotropin-releasing hormone (TRH 7) (Fig. 15.4) with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous, and some method is needed to exclude potential conformers. Modem biophysical methods, e.g., X-ray crystallography or isotope edited nuclear magnetic resonance (NMR), (33) can be used to characterize peptide-protein interactions for soluble proteins, but most biophysical methods cannot yet determine the conformation of a ligand bound to constitutive receptors, e.g., G-protein-coupled receptors (34, 35). 

The work of Veber et al. established that valuable information about the bioactive conformation of a flexible peptide could be obtained by applying the principles of conformational restriction, and several additional examples soon were reported that followed this strategy. Conformationally restricted enkephalin analogs, e.g., 02-13), were formed by cyclizing between positions 2 and 5 of enkephalins (4a-b) (39). Cyclization of a-mela-notropin (14) gave the unusually active analog... 

Peptide chemists routinely apply conformational restriction in their attempts to determine possible bioactive conformations. 

Flexible peptides can be conformationally restricted by a variety of methods other than macrocyclization of the peptide. 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 (42) these types of approaches led to his "Active Analog" approach for determining bioactive conformations of flexible molecules (43). Some other traditional... 

Conformational restriction has also been used to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett et al. (49) synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin converting enzyme (ACE)inhibitors enalapril (20) and enalaprilat (21) (Fig. 15.9) to characterize torsion angles in the bioactive conformation. Analog (22) was used to constrain the torsion angle psi (T ). Flynn et al. 

Moeller and coworkers have made extensive use of the anodic a-alkoxylation of amides [27-31]. Much of their work has focused upon the synthesis of conformationally restricted peptide mimetics in an effort to ascertain the relationship between the bioactivity of the parent peptide and a specific conformer of it. The example illustrated in Scheme 8 portrays an exceptionally clever synthesis of 94, a key substance en route to the Phe-Pro building block 95 [28]. Both the electrooxidation and ring-forming metathesis (93 to 94) reactions are of special note. 

The principle of conformational restriction was first applied to characterize the bioactive conformation of acetyl choline acting at the muscarinic and nicotinic receptors. Conformational restriction has been applied to many other small ligands (e.g. see reviews by Martin-Smith et al., Portogh-ese, Mutschler and Lambrecht, and Casy et but the work on acetylcholine analogs exemplifies the necessary ideas and techniques required to understand the general approach, as well as its strengths and limitations, when applied to small molecules. 

Conformationally restricted analogs of other low molecular mass agonists have been synthesized or discovered in attempts to characterize the bioactive conformation of the ligand., This field is vast and selected examples of constrained agonist analogs of dopamine (23.10) versus (23.11), GABA (23.12) versus (23.13)-(23.14),2 glutamic acid (23.15) versus (23.16) and (23.17), histamine (23.18) versus (23.19) and (23.20), serotonin (23.21) versus (23.22) that have been discovered by application of this approach are shown in Fig. 23.2. 

The work of Veber and coworkers established that valuable information about the bioactive conformation of a flexible peptide could be obtained by applying the principles of conformational restriction, and several additional... 

Conformational restriction played an important role in the discovery that water induces the bioactive conformation of CsA. Cyclosporin A (Sandimmune , CsA, (23.37), Fig. 23.7), is a major drug for preventing rejection of transplanted human organs and has been the subject of many synthetic, conformational and mechanism of action studies. To produce immunosuppression, CsA first binds to cyclophilin A (CyP A), a peptidyl prolyl cis-trans isomerase (PPIase), to form the CsA-CyP complex, which then binds to and inhibits calcineuiin (CaN), a calmodulin-dependent serine/threonine protein phosphatase, thereby inhibiting interleukin-2 (IL-2) synthesis. ... 

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