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

Abstract

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 Ca 2+ 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.

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

“…Furthermore, these results are in consonance with earlier reports that mentioned isoindolinone derivatives majorly as regulators of Cyclins and CDKs and modulator of PI3K-Akt-dependent G1 arrest. 21 , 37 , 38 This could be probed further to evaluate Cyclins and CDKs as the molecular targets of these 3-methyleneisoindolinones.…”

“…In silico ADME profiling of representative compounds revealed their drug-likeness properties, and the synthesized compounds fulfill the criteria to be a drug candidate. Further, earlier reports have mentioned isoindolinone derivatives as inhibitors of MDM2-p53 interactions, regulators of Cyclins and CDKs, inhibitors of PARP-1, and modulator of PI3K-Akt-dependent G1 arrest. ,,,, The role of tumor suppressor p53 in regulation of cell cycle and apoptosis is well known, and MDM2-p53 axes have been reported to be involved in onsets of HNSCC. − Additionally, Tp53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes the MDM2-p53 axis an attractive target point to improve HNSCC therapy by modulation of tumor suppression activities and apoptosis.…”

“…Further, earlier reports have mentioned isoindolinone derivatives as inhibitors of MDM2-p53 interactions, regulators of Cyclins and CDKs, inhibitors of PARP-1, and modulator of PI3K-Akt-dependent G1 arrest. 21 , 37 , 38 , 44 , 45 The role of tumor suppressor p53 in regulation of cell cycle and apoptosis is well known, and MDM2-p53 axes have been reported to be involved in onsets of HNSCC. 46 − 48 Additionally, Tp53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells.…”

Photo-induced synthesis, stereochemistry and antitumor activity of valine-based small cyclopeptides

“…Our team focused on the structural modification of various a Key Laboratory for Photonic and Electronic Bandgap Materials (Ministry of natural peptides by IPETC reactions to develop novel antitumor agents. [11][12][13] We found that many of the compounds with an isoindolinone moiety showed good antitumor activitiy. We have also observed that the IPETC synthesis of cyclic peptides starting from chiral pure amino acids can generate chiral pure products (mainly the C-3 chiral center), since the chiral starting material may significantly affect the spatial properties of the precursor in the cyclization reaction.…”

“…12,14 The structural modification of natural cyclic peptides phakellistatin 2, phakellistatin 6 and fenestin A also showed that the compounds with the same amino acid sequence yet different spatial structural features presented disparate antitumor activities. 11,13,15 It has been reported that introduction of methylated Pro residues into the peptide would increase the percentage of the cis conformation of Pro and rescue the biological activity from synthetic cyclopeptides. 16 Therefore, we here attempt to investigate the effect of chiral amino acids on the chiral character of C-3 in isoindolinone and on the bioactivity.…”