Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13,Journal of Medicinal Chemistry

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Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-11 , DOI: 10.1021/acs.jmedchem.4c00393
Tong Li ₁ , Shitian Jiang ₁ , Tingting Li ₁ , Hongyu Xu ₁ , Xiong Zhang ₁ , Rui Yan ₁ , Xiaodan Wu ₁ , Yingxue Jin ₁ , Zhiqiang Wang ₁

Affiliation

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.

中文翻译：

探索天然大环肽 Phakellistatin 13 衍生的环肽基抗肿瘤药物的潜力

基于天然环肽的新型抗癌化合物的探索已成为当代大环药物发展的关键范例。 Phakellistin 13是一种从棕色粗海绵中提取的环七肽，具有显着的抗肿瘤活性。在本研究中，我们设计并合成了一系列在天然环七肽 Phakellistin 13内不同位点结合刚性异吲哚酮部分的手性环肽，目的是研究构象受限的环肽作为潜在的抗肿瘤药物。环肽3包含交替的l- / d-氨基酸残基，表现出有希望的抗肝细胞癌作用。详细的生物学实验表明，Phakellistatin 13类似物可有效抑制肿瘤细胞的增殖并诱导细胞凋亡和自噬，同时还通过调节 p53 和丝裂原激活蛋白激酶 (MAPK) 信号通路引起细胞周期停滞。这项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了解天然环肽药物开发的生物学机制。

更新日期：2024-07-11

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