Novel Isoindolinone-Based Analogs of the Natural Cyclic Peptide Fenestin A: Synthesis and Antitumor Activity.

Small- and medium-sized cyclopeptides have been found to have extensive bioactivities and have drawn much attention from medicinal chemists. In the work described in this paper, various cyclic peptide analogs of Fenestin A were synthesized by intramolecular photoinduced electron-transfer cyclization reactions to study the influence of slight structural changes on the bioactivity of small cyclopeptides. The incorporation of thiazole and rigid isoindolinone fragments was found to improve the bioactivity of the cyclopeptide. Detailed in vitro studies of the apoptosis mechanism, mitochondrial membrane potential, cell cycle, intracellular Ca2+ concentration, and lactate dehydrogenase activity following treatment with a cyclopeptide showed that the cyclopeptide could induce apoptosis of tumor cells and lead to cycle arrest in the G2/M phase. The research also suggested that the photoinduced reaction could be applied to construct cyclic peptides stereoselectively, and the introduction of rigid fragments could enhance the biological activity of cyclopeptide drugs.

Photoinduced Synthesis of Methylated Marine Cyclopeptide Galaxamide Analogs with Isoindolinone as Anticancer Agents.

The methylation of amino acid residues has played an important role in the biological function of bioactive peptides. In this paper, various methyl-modified and stereostructural-modified marine cyclopeptide galaxamide analogs with isoindolinone were synthesized by a photoinduced single electron transfer cyclization reaction. It was found that the single-methyl substitution was beneficial for the bioactivity of cyclic analogs with isoindolinone fragments, and the influence of methylation on bioactivity is uncertain and is sometimes case-specific. The compound with a single methyl group at Gly5 (compound 8) showed the strongest antiproliferative activity against HepG-2 cells. The tumor cell apoptosis, cell cycle, mitochondrial membrane potential, intracellular Ca2+ concentration and lactate dehydrogenase activity have been studied extensively to evaluate the antitumor potential of compound 8. Western blotting tests showed that compound 8 could decrease the MDM2 level and increase p53 levels efficiently. Careful molecular docking suggested that cyclic peptide 8 could bind firmly with MDM2 oncoprotein, indicating that MDM2 may be a potential drug target of the prepared peptides.