Cyclic Dipeptide: A Privileged Molecular Scaffold to Derive Structural Diversity and Functional Utility

Abstract

Cyclic dipeptides (CDPs) are the simplest form of cyclic peptides with a wide range of applications from therapeutics to biomaterials. CDP is a versatile molecular platform endowed with unique properties such as conformational rigidity, intermolecular interactions, structural diversification through chemical synthesis, bioavailability and biocompatibility. A variety of natural products with the CDP core exhibit anticancer, antifungal, antibacterial, and antiviral activities. The inherent bioactivities have inspired the development of synthetic analogues as drug candidates and drug delivery systems. CDP plays a crucial role as conformation and molecular assembly directing core in the design of molecular receptors, peptidomimetics and fabrication of functional material architectures. In recent years, CDP has rapidly become a privileged scaffold for the design of advanced drug candidates, drug delivery agents, bioimaging, and biomaterials to mitigate numerous disease conditions. This review describes the structural diversification and multifarious biomedical applications of the CDP scaffold, discusses challenges, and provides future directions for the emerging field.

Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

“…The scaffold is the main fragment of compound (e.g., ring system) after removal of substituents (R-groups) [71,72]. The privileged molecular scaffold is defined as a core structure, which forms structurally diverse bio-molecules via introducing different functional groups [73,74]. DKPs can play the role of a privileged, multi-functionalized scaffold for the design and development of advanced therapeutic agents, drug delivery systems, biomaterials, or bio-imaging to mitigate numerous disease conditions, also as for the synthesis of complex natural products [74] because of their specific conformational and physico-chemical attributes.…”

“…The privileged molecular scaffold is defined as a core structure, which forms structurally diverse bio-molecules via introducing different functional groups [73,74]. DKPs can play the role of a privileged, multi-functionalized scaffold for the design and development of advanced therapeutic agents, drug delivery systems, biomaterials, or bio-imaging to mitigate numerous disease conditions, also as for the synthesis of complex natural products [74] because of their specific conformational and physico-chemical attributes. DKPs are heterocyclic compounds consisting of two amino acid residues linked to a central six-membered lactam ring core with (or without) various substituents, providing the control of the substituent's stereochemistry at up to four positions, chiral nature, three-dimensionality, and consequently leading to the promotion of the intermolecular H-bonding interactions with bio-target sites via the corresponding sites of donors and acceptors [17].…”

“…Compounds 72 and 73 were tested for cytotoxic effect on four cancer cell lines: MV4-11, K562, HL-60, and A549 and exhibited selective cytotoxic effect against leukemic MV4-11 cell line with IC 50 values of 7.2 µM and 10.0 µM, respectively (Table 5, entries 4,5). (+)-Avrainvillamide (74), isolated from the fermentation broth of Aspergillus ochraceus [87], turned out to be a potent inhibitor of tumor-associated protein-nucleoplasmin [139,140] overexpressed in many human tumors, exhibiting strong cytotoxic effect against HeLa (IC 90 [µg/mL] = 1.1) [87], T-47D (breast cancer, GI 50 [µM] = 0.33), and LNCaP (GI 50 [µM] = 0.42) cell lines [139] (Table 5, entry 6). Its enatiomer 75 exhibited a weaker, but still potent cytotoxic effect, when tested on T-47D and LNCaP cell lines with GI 50 [µM] values of = 0.91 and 1.4, respectively (Table 5, entry 7) [140].…”

“…Its enatiomer 75 exhibited a weaker, but still potent cytotoxic effect, when tested on T-47D and LNCaP cell lines with GI 50 [µM] values of = 0.91 and 1.4, respectively (Table 5, entry 7) [140]. (+)-Avrainvillamide (74) was further investigated as a potential antileukemic agent [140] and tested on five acute myeloid leukemia (AML) cell lines: NB4, HL-60, MV4-11, OCI-AML3, and Molm-13 giving IC 50 [µM] values from 1.1 (NB4) to 0.078 (Molm-13). Waikikiamide A (76) and Waikikiamide B (77) were isolated from a Hawaiian marine fungal strain Aspergillus sp.…”

Self-Assembly Dipeptide Hydrogel: The Structures and Properties

“…The strategies for preparing the new generation of dipeptide hydrogels can be divided into four categories based on the modification site of dipeptide: 1) N-terminal modified dipeptide; 2) C-terminal modified dipeptide; 3) uncapped dipeptide; 4) cyclic dipeptide. This review will focus on the linear dipeptide (1-3) and other recent reviews about cyclic dipeptide can be found in articles by Yu et al (2020) and Balachandra et al (2021).…”