Structure Modification And Antitumor Activity Study Of Natural Cyclic Peptide Hikiamide B

The development of novel and highly effective anti-cancer drugs is the focus of research in the medical community today.In recent years,cyclic peptide drugs have attracted much attention for their structural diversity,low inherent toxicity,high selectivity,affinity for protein targets and rich functionality.The cyclic peptide Hikiamide B is a cyclic pentapeptide isolated from Fusarium oxysporum with agonistic effects on peroxisome proliferator-activated receptorγ(PPARγ)and has potential antitumor effects.This paper used Hikiamide B as a precursor for structural modification.Since the ester bond is readily hydrolyzed by carboxylesterases in vivo,we replaced S-OLeu in the precursor structure with L-Leu and inserted phthalimide groups at different positions without changing the amino acid sequence of the peptide chain,and photo-induced single electron transfer(SET)cyclic peptide synthesis reaction with phthalimide The light-induced single electron transfer(SET)cyclic peptide synthesis reaction,using phthalimide as the electron donor and a peptide chain containing N-trimethylsilyl benzylamine as the electron donor,resulted in an intramolecular donor-acceptor system,generating double-terminated radicals and cycling to obtain a series of Hikiamide B analogs.NMR and MS characterized the structure of the product.A combination of electron circular dichroism(ECD)and theoretical calculations determined the C-3(C-3-R/C-3-S)absolute configuration during cyclization.Antitumor activity of Hikiamide B analogs assessed by MTT assay.In order to investigate the pattern of C-3 chiral production during the reaction,a series of small cyclic peptides containing different amounts and conformations of(D-or L-)valine were designed and prepared by photoinduced single electron transfer reactions.This suggests that the C-3 chiral center of cyclic peptides is strongly influenced by the configuration of nearby Val~2 residues.In contrast,there was no significant correlation between Val~3 and Val~4 and the C-3 conformation.Therefore,we suggest that the C-3 conformation of cyclic peptides prepared by photoinduced SET reactions is influenced to some extent by the chirality of neighboring amino acids,facilitating the design and synthesis of cyclic peptides with specific conformations.Furthermore,screening of the antitumor activity of the prepared cyclic peptide against Hep G-2 cells by MTT.