Pushing peptides further: Novel methodologies for the synthesis of backbone-modified peptides

[eng] Peptides and proteins are essential substances for living organisms, as they can be found in every cell and tissue and are involved in many biological and physiological processes. Given their intrinsic properties and their attractive pharmacological profile, they have emerged as potential tools for drug discovery. However, in vivo instability due to protease degradation and poor bioavailability are the main drawbacks that have hampered their exploitation as therapeutic agents. Of special interest are peptide-based molecules displaying peptide backbone modifications, since they often result in improved pharmacological properties, such as greater stability and bioavailability, enhanced cell permeability and lower toxicity. Among the most relevant types of bioactive backbone-modified peptide families, depsipeptides and stapled peptides are included. In this context, the work presented herein was focused on the development of novel methodologies for the synthesis of depsipeptides and stapled peptides. Up to date, the most general and effective strategy for the preparation of complex cyclodepsipeptides combines solid-phase synthesis and solution chemistry approaches, in which segment condensation is used for the assembly of the building blocks containing the depsipeptide moieties. However, this methodology presents some disadvantages. For instance, the synthetic route must be designed and optimised for each particular case, and therefore a versatile general synthetic method cannot be outlined. Thus, a robust full solid-phase methodology would become a valuable chemical tool for both the preparation of naturally-occurring cyclodepsipeptides and the rapid generation of synthetic analogues. With that purpose, a synthetic analogue of naturally-occurring cyclodepsipeptide YM-254890 was used as a model depsipeptide for the development of such methodology, where the drawbacks commonly encountered during solid-phase depsipeptide synthesis, including: DKP formation, formation of undesired α,β-elimination side-products during Fmoc removal and selection of the optimal protecting group scheme, were extensively studied and solved. Additionally, evaluation of the strategy efficiency was carried out by comparison with conventional segment condensation approaches. Remarkably, similar overall yields as the ones obtained for segment condensation approaches were observed. Thus, the newly developed methodology becomes a versatile and convenient tool for the preparation of co