Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13

The exploration of novel anticancer compounds based on
natural
cyclopeptides has emerged as a pivotal paradigm in the contemporary
advancement of macrocyclic pharmaceuticals. Phakellistatin 13 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 13, 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 13 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.

基于天然环状肽的新抗癌化合物的探索已成为宏观环状药物当代进步中的关键范式。Phakellistatin 13 是一种从棕色短柄海绵中提取的环庚肽，表现出显著的抗肿瘤活性。在本研究中，我们设计并合成了一系列手性环状肽，这些肽在天然环庚肽 Phakellistatin 13 的不同位置引入了刚性的异喹啉酮基团，旨在研究构象受限的环状肽作为潜在的抗癌药物。含有交替的 l-/d-氨基酸残基的环状肽 3 显示出有前景的抗肝细胞癌效果。详细的生物实验揭示了 Phakellistatin 13 类似物能够有效抑制肿瘤细胞的增殖，并诱导细胞凋亡和自噬，同时通过调节 p53 和细胞因子激活的蛋白激酶（MAPK）信号通路导致细胞周期阻滞。本研究不仅为化学结构修饰提供了宝贵的见解，而且有助于更深入地理解基于天然环状肽药物发展的生物学机制。