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A facile methodology for the synthesis of bicyclopeptides containing isoindolone was developed by an intramolecularly photo-induced electron transfer cyclo-reaction (IPETC) with high yield and stereoselectivity. Nine bisulfide-bridged bisisodindolone–cyclopeptides were successfully prepared based on the construction of an intramolecular bis-(donor–acceptor) electron system using L -cystine as the linker. The stereostructures of the bicyclopeptides were determined by ECD and 13C-NMR spectra combined with quantum chemistry calculations. The research provided a possible solution for the preparation of multi-cyclopeptides with complex and rigid cyclic structures by introducing cysteine moieties into linear peptides. [ABSTRACT FROM AUTHOR]

• A facile methodology for novel cyclopeptide p53-MDM2 inhibitors with isoindo-linone synthesis has been developed based on photo-induced single electron transfer reaction (SET). • The effect of compound 1 on mitochondrial membrane potential and intracellular Ca2+ concentration have been studied extensively to evaluate the antitumor potential. • The molecular docking suggested that compound 1 presented stronger binding with MDM2 oncoprotein of liver cancer cells, and indicating that compound 1 is a potential inhibitor of MDM2 interactions. In this paper, two kinds of novel p53 cyclopeptides containing 1-Phe, 2-Trp, 3-Leu, 4-Leu/Pro residues and isoindolinone were synthesized by intramolecular photoinduced single electron transfer cyclization reactions, and their structures were confirmed by 1H NMR, 13C NMR and HR-MS. Comparison of bioactivity of compound 1 and 2 against HeLa, HepG-2, MDA-MB, MCF-7 and 4T1 cell lines by MTT assay, indicated moderate antiproliferative activity of compound 2 (4-Pro). Moreover, compound 1 (4-Leu) with isoindolinone fragments exhibited the strongest antiproliferative activity against HepG-2 cell line with an IC 50 of 9.54 μg/mL. The effect of compound 1 on mitochondrial membrane potential and intracellular Ca2+ concentration have been studied to evaluate the antitumor potential. The decrease of mitochondrial membrane potential and the increase of intracellular Ca2+ concentration indicated compound 1 had the excellent antitumor activity. Especially for compound 1 , the molecular docking suggested that 4-Leu residue and isoindolinone fragments presented stronger binding with MDM2 oncoprotein of liver cancer cells, which plays an important role in the stability of MDM2 ligands. [Display omitted] [ABSTRACT FROM AUTHOR]