Synthesis of new peptide-based macrocycles: Evaluation of their in vitro anti-proliferative activity and molecular dynamic simulation studies

Abstract

A simplified synthetic protocol was adopted for the preparation of the six novel cyclo-pentapeptide candidates of the structure cyclo-(m-phthaloyl)-bis-[L-Phe -Gly/Sar]-L-Lys–X, where X = COOMe (9a,b), COOH (10a,b) and NHNH2 (11a,b). The potential cytotoxicity (IC50, μg/mL) for cyclo-pentapeptides (9a,b), (10a,b), (11a,b) and doxorubicin® as reference drugs, is assayed against eight cell lines of human cancer namely; mamillary MCF-7 and T47D, hepatic HEPG2, colon HCT116, cell line of cervix HELA, larynx HEP2, Prostate PC3, and gut Caco. Cyclo-[m-phthaloyl chloride-bis-(L-phalanine-sar)-L-Lys]-COOH 10b was proved as cytotoxically more potent than doxorubicin against most of the screened cell lines. It can be inferred that the proposed molecular structural characteristics associated with cytotoxicity in these m-phthaloyl-bridged cyclopeptides appear noteworthy and hold promise as potential candidates for further exploration as novel anticancer agents. Molecular dynamics simulation studies of 10b into the binding site of Human Epidermal Growth Factor Receptor tyrosine kinase exhibited the highest MM-GBSA value (-16.59 kcal/mol). KEY WORDS: Anticancer, Cytotoxicity, Cyclopeptides, Cyclopeptides, m-phthaloyl-bis-peptides Bull. Chem. Soc. Ethiop. 2024, 38(4), 1129-1144. DOI: https://dx.doi.org/10.4314/bcse.v38i4.25