Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin <b>13</b>

The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin <b>13</b> is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin <b>13</b>, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin <b>13</b> analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.