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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]

Photoinduced single electron transfer (SET) cyclization processes for synthesis of a Sansalvamide A analog containing double pharmacophores (cyclicpeptides and O-phthalimide moiety) is described to develop novel antitumor cyclopeptide drug. The resultant compound is active in drug-sensitive HeLa, HepG-2 and MCF-7 cell lines. Specifically, the title compound was found to inhibit MCF-7 cells with an IC 50 value of 15 μM (13.4 μg/mL), which may serve as a potential candidate for antitumor drug development. [ABSTRACT FROM AUTHOR]

Cyclic peptides has become an attractive modality for drug development due to their excellent binding affinity, target selectivity and low toxicity, however significant activity difference between the synthetic and natural cyclic peptides such as Phakillestatins has puzzled chemists for years. In an effort to explore the bioactive secondary structures, three pairs of cyclic Phakellistatin 6 analogs with special constrained stereo-features were prepared by regioselectively controlled intramolecular photoinduced single electron transfer (SET) reactions in this paper. The spatial configurationally features were systematically investigated by ECD and NMR, together with detailed structural analysis based on theoretical calculations, which showed that conventional turns rather than irregular γ-/β-turn secondary structures played important roles for the antitumor activities. We also presented the in vitro bioactive assay, liposomal leakage assays and electron microscopy analyses, which indicated the prepared cyclopeptide analogs excellent antitumor activities, most showing greater growth inhibitory effects than that of the famous anticancer agent paclitaxel. Image 1 • Novel Phakellistatin 6 analogs were stereoselectively synthesized by photoinduced cyclization. • Their absolute configurations were determined by experimental and theoretical ECD spectra. • The spatial configurationally features affecting the antitumor activities were elucidated in detail. [ABSTRACT FROM AUTHOR]