Abstract
A critical summary on the discovery of the nineteen members of the phakellistatin family (phakellistatin 1–19), cytotoxic proline-rich cyclopeptides of marine origin, is reported. Isolation, structural elucidation, and biological properties of the various-sized natural macrocycles are described, along with the total syntheses and the enigmatic issues of the cytotoxic activity reproducibility.
Highlights
Marine organisms are an impetuous reservoir of intriguing natural products [1]
Because of the ambiguities about the actual biological source and their poor natural availability, the evaluation of the biological potential of these promising bioactive peptides frequently has to await the accomplishment of a suitable synthetic route. For these natural compounds the total synthesis still plays a central role in developing their therapeutic potential, confirming the correct structural assignment of the isolated active compound [18]
Proline-rich cyclopeptides belong to a captivating class of natural compounds with a wide range of biological functions
Summary
Marine organisms are an impetuous reservoir of intriguing natural products [1]. Over billions of years of evolution, the bioactivities of these secondary metabolites have been finely tuned and still, today, they represent an unrivaled source of inspiration for the discovery of new drugs: from antiviral, to antibiotic, to cytostatic, to antitumor qualities [2,3]. The reduced flexibility due to macrocyclization, heterocyclization, or cross-linking generally enhances active three-dimensional structures favoring specific binding with proper biological targets [13,14] Another intriguing feature of cyclic peptides/depsipeptides is represented by the presence of unusual amino acids, such as β-hydroxylated, N-alkylated, D-amino acids, or heterocyclic moieties (oxazolines, oxazoles, thiazolines, and thiazoles, which come from amino acids, such as Ser/Thr and Cys), alternated within standard amino acid sequences. Because of the ambiguities about the actual biological source and their poor natural availability, the evaluation of the biological potential of these promising bioactive peptides frequently has to await the accomplishment of a suitable synthetic route For these natural compounds the total synthesis still plays a central role in developing their therapeutic potential, confirming the correct structural assignment of the isolated active compound [18]. The development of an efficient total synthesis can allow the introduction of artificial modifications yielding more active analogues
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