Target-based anticancer glycyrrhetinic derivatives: Design, synthesis, biological assessment and molecular docking studies

Abstract

18-Glycyrrhetinic acid (GA) is regarded as the principal active component isolated from the Chinese medicinal plant of licorice root, and it has considerable anticancer actions. This work was built on the discovery and design of brand-new 18-glycyrrhetinic acid (GA) amino acid peptides and peptide ester analogs. The cytotoxic evaluation exhibited that despite the promising cytotoxic activity of the tested peptides 2, 3, 4, 6, and 7 in MCF-7 and HCT-116 cancer cells, with IC50 values ranging from 5.1-7.4 and 6.6-72.7 µg/mL, respectively. Furthermore, all freshly produced GA-peptides with moderate to high activity on tumor cell lines produced a favorable safety profile versus typical human dermal fibroblasts (BJ-1) cellular lineage. Interestingly, 2, 4 and 6 demonstrated excellent multitargeting inhibitory profiles against CDK-2, VEGFR-2, and PDGFR-α kinases. Moreover, since peptide 6 was the most active cytotoxic agent, it was chosen as an illustrative candidate to examine its influence on many apoptotic markers in invitro studies, including Bax, caspase-3 and 7, DNA fragmentation, BCl-2, p53, and tubulin polymerization inhibition. All novel analogs were tested for their antimicrobial efficacy versus a panel of microbial strains. The peptide 6 was also subjected to molecular docking simulations in the active sites of the prior kinases. KEY WORDS: Peptides, Glycyrrhetinic acid, Anticancer, Cytotoxicity, Molecular docking, Antimicrobial activity Bull. Chem. Soc. Ethiop. 2024, 38(5), 1369-1392. DOI: https://dx.doi.org/10.4314/bcse.v38i5.14