A Highly Practical RCM Approach towards a Molecular Building Kit of Spirocyclic Reverse Turn Mimics

Abstract

The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI beta-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II beta turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-membered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic epsilon-lactam 12 closely agrees with the reference gamma-lactam 3 a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3 b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II beta turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.

In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study

“…The biologically active sequence is the C-terminal part NT(8–13) (Arg-Arg-Pro-Tyr-Ile-Leu) [2] which binds to the three neurotensin receptor subtypes NTS1, NTS2, NTS3 [3] and has therefore been selected as a lead structure for medicinal chemists [4,5,6,7,8,9,10,11,12,13]. The NTS1 is upregulated in various tumor types including prostate, pancreas, mamma, lung and colon carcinoma [14,15,16].…”

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

“…Finally, an aqueous solution with 30% tert-BuOH as cosolvent with a high catalyst loading (50 equiv HG2) in the presence of a large excess of MgCl 2 (5000 equiv), to suppress ruthenium-peptide adduct formation, at 37 C for 24 h, ultimately resulted in a successful RCM of 95d and 96d, since their cyclic congeners were isolated in 78% and 63% yield, respectively ( Table 1). The authors conclude that "the sulfur atom within S-allylcysteine drastically improved the efficiency of RCM compared to pentenylglycine and O-allylserine analogs" and that their method provides "an alternative to the on-resin cyclization of S-allylcysteine, which is particularly attractive in instances where on-resin cyclization is not possible" [129].…”

“…Of special interest are type IIc cyclic constraints since they constitute potent type II β-turn-inducing molecular scaffolds [37]. In this context it is important to mention the contributions of the Moeller [38], respectively, Wagner [39] and Schmalz groups since they showed that stereo-and regiospecific functionalization of the proline ring with suitable alkene moieties is a powerful tool to define the conformation of the fused pyrrolidine ring as polyproline type II (PPII) helix mimic [40] or as an α-helix-nucleating motif [41] to stabilize the secondary structure of relatively small peptide sequences (vide infra).…”

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

“…[78] An alternative class of b-turn mimetics are spirocyclic compounds (4, Figure 4) initially described by Robinson and co-workers [79] and analyzed in detail by Gmeiner and coworkers. [80][81][82] Recently, trans-pyrollidine-3,4-dicarboxamide (5, Figure 4) was shown to mimic b-turns that harbor proline at position i + 1. [83] Notably, Müller et al re-analyzed some of the described turn mimetics in detail and suggested that not all categorized scaffolds recapitulate the anticipated turn structures correctly.…”