Abstract
Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.
Highlights
Cyclic dipeptides, known as cyclo-dipeptides, diketopiperazines (DKPs), piperazinediones, dioxopiperazines, or dipeptide anhydrides, are the simplest, naturally occurring cyclic forms of peptides, commonly biosynthesized by a large variety of living organisms [1,2,3,4] and conserved in bacteria to humans [5,6]
DKP skeleton is observed in micro-species, bacteria, such as Bacillus subtilis, Streptomyces, Pseudomonas aeruginosa, or Lactobacillus plantarum [38,39,40], marine, and terrestrial fungi [41] as Aspergillus flavus or Alternaria alternata, and Penicillium, respectively [42,43], marine sponges such as Dysidea herbacea, and fragilis [44], or proteobacteria Alcaligenes faecalis, algae, lichens, gorgonians, tunicates, plants, or animals venoms
Lin [107] reported that cyclo (L-Leu-L-Pro) (3), isolated from Streptomyces xiamenensis MCCC 1A01570, evaluated for cytotoxicity against three cancer cell lines of ECA-109, HeLa-S3 and PANC-1 exhibited moderate inhibition effect at 20 μM varying from 14% (PANC-1) to 55% (ECA-109) (Table 1, entry 3)
Summary
Known as cyclo-dipeptides, diketopiperazines (DKPs), piperazinediones, dioxopiperazines, or dipeptide anhydrides, are the simplest, naturally occurring cyclic forms of peptides, commonly biosynthesized by a large variety of living organisms [1,2,3,4] and conserved in bacteria to humans [5,6]. Proline-based DKPs have diverse properties depending on structure and application, such as anticancer, antioxidant, neuroprotective, antiviral, antibacterial, anti-inflammatory, antihyperglycemic, antiarrhythmic, immunomodulatory, antiparasitic, anthelmintic, insecticidal, antifouling, vasorelaxant, and metabolic regulatory activity [16,17,18,19,20,21,22] They have the potential to be antibiotics of the future. We present a comprehensive overview of the recent progress on bio-landscape and structural diversity of compounds containing proline-based DKP motif, which are exploited as privileged peptidomimetic scaffolds for future innovative drug discovery, smart delivery systems, and modern bio-control agents [34,35,36]. The supramolecular structuring and the role of versatile synthons for inspiration in the design of compound libraries in search of ideal ligands with unique proline-DKP motif are discussed
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