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Marine cyclic peptides have become an important source for drug development. In this work, two novel cyclic peptide zygosporamide analogs with the isoindolinone fragment were prepared, which have broad-spectrum antitumor activity. We have tried to compare their bioactivities by changing the amino acid (R-3Leu and S-4Leu) configuration. Notably, compound 8, with R-3Leu and S-4Leu residues, showed better inhibiting ability than that of compound 9, which contains S-3Leu and R-4Leu residues. Furthermore, careful molecular docking indicated that compound 8 presented stronger binding with the EGFR protein of liver cancer cells, providing an explanation for the difference in bioactivity. This research has provided a useful guide for peptide-based drug-target design. [ABSTRACT FROM AUTHOR]

Photoinduced single electron transfer cyclization processes for synthesis of a series of 3‐hydroxy isoindolinone cyclotripeptides containing double pharmacophores (cyclotripeptides and phthalimide moiety) are described to develop novel antitumor cyclopeptide drugs. The results showed that our proposed method could be used to synthesize various isoindolinone cyclotripeptides highly regioselectively at a moderate rate. Moreover, the inhibitory potency toward human cervical carcinoma HeLa cells of the target cyclopeptides and the linear tripeptide precursors were evaluated, and most of the compounds were observed with potent inhibition ability against tumor growth. Specifically, compound 6c was found to inhibit HeLa cells with an IC50 value of 32 μM, which may serve as a potential candidate for drug development. In addition, 3‐hydroxy isoindolinone‐cyclo‐Gly‐Ala‐Pro (6a1) was chosen from the obtained cyclopeptides for the absolute configuration research, and an S configuration of C‐3 was established by experimental electronic circular dichroism with the aid of theoretical calculations. [ABSTRACT FROM AUTHOR]

Two novel Fenestin A analogs (1 and 2) containing a phthalimide moiety are prepared by photoinduced cyclization. Their absolute configurations were determined by experimental ECD with the aid of theoretical calculations. The resulting compounds are active in HeLa (IC50 = 28.2 μM for 1 and 36.5 μM for 2) and HepG-2 cell lines (IC50 = 33.5 μM for 1 and 40.3 μM for 2). [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]