Natural epidithiodiketopiperazine alkaloids as potential anticancer agents: Recent mechanisms of action, structural modification, and synthetic strategies

• Published in: Bioorganic chemistry 2023-08, Vol.137, p.106642-106642, Article 106642
• Main Authors: Wang, Lin, Jiang, Qinghua, Chen, Siyu, Wang, Siyi, Lu, Jingyi, Gao, Xun, Zhang, Dongfang, Jin, Xin
• Format: Article
• Language: English
• Subjects: Alkaloids - chemistry; Anticancer activity; Antineoplastic Agents - chemistry; Epipolythiodioxopiperazine alkaloids; Humans; Mechanisms of action; Neoplasms - drug therapy; Phosphatidylinositol 3-Kinases; Structural modification; Synthetic strategies
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106642

[Display omitted] •The sources, classification, structural characteristics, and anticancer potential of natural epidithiodiketopiperazine (ETP) alkaloids are summarized (1970–2023).•The mechanisms of action of several ETP alkaloids with anticancer activity are reviewed (2009–2023).•The structural modifications and synthetic strategies for several ETP alkaloids with anticancer activity are listed (2009–2023).•This review highlights the tremendous potential of ETP alkaloids and their derivatives as lead compounds for further anticancer drug development. Cancer has become a grave health crisis that threatens the lives of millions of people worldwide. Because of the drawbacks of the available anticancer drugs, the development of novel and efficient anticancer agents should be encouraged. Epidithiodiketopiperazine (ETP) alkaloids with a 2,5-diketopiperazine (DKP) ring equipped with transannular disulfide or polysulfide bridges or S-methyl moieties constitute a special subclass of fungal natural products. Owing to their privileged sulfur units and intriguing architectural structures, ETP alkaloids exhibit excellent anticancer activities by regulating multiple cancer proteins/signaling pathways, including HIF-1, NF-κB, NOTCH, Wnt, and PI3K/AKT/mTOR, or by inducing cell-cycle arrest, apoptosis, and autophagy. Furthermore, a series of ETP alkaloid derivatives obtained via structural modification showed more potent anticancer activity than natural ETP alkaloids. To solve supply difficulties from natural resources, the total synthetic routes for several ETP alkaloids have been designed. In this review, we summarized several ETP alkaloids with anticancer properties with particular emphasis on their underlying mechanisms of action, structural modifications, and synthetic strategies, which will offer guidance to design and innovate potential anticancer drugs.