从食用药用真菌阿魏菇中分离得到的过氧化麦角甾醇（EP）具有广泛的抗肿瘤活性，但其水溶性差和生物利用度低限制了进一步的应用。在这项研究中，EP 使用三苯基膦 (TPP) 进行结构修饰，结合了线粒体靶向性、两亲性和细胞毒性。合成了一系列具有不同长度连接臂的TPP-缀合的麦角甾醇过氧化物衍生物(TEn)。构效关系表明，随着连接臂的伸长，TEn的抗癌活性逐渐降低。化合物 TE3 具有最佳和最广泛的抗肿瘤作用。主要通过靶向线粒体，诱导ROS产生，破坏线粒体功能，激活线粒体凋亡途径来发挥抗宫颈癌活性。其中，TPP仅作为线粒体靶向基团，而含有过氧化物桥结构的EP作为诱导ROS的活性基团。体内实验表明，TE3比一线抗癌药物顺铂具有更好的抗宫颈癌活性和安全性，并能激活小鼠的免疫反应。尽管 TE3 表现出一些急性毒性，但在治疗剂量下并不显着。因此，TE3作为抗宫颈癌药物具有进一步开发的潜力。版权所有©2024 The Authors。由爱思唯尔公司出版。保留所有权利。

Ergosterol peroxide (EP) isolated from the edible medicinal fungus Pleurotus ferulae has a wide range of anti-tumor activity, but poor water solubility and low bioavailability limit further application. In this study, EP was structurally modified using triphenylphosphine (TPP+), which combines mitochondrial targeting, amphiphilicity, and cytotoxicity. A series of TPP+-conjugated ergosterol peroxide derivatives (TEn) with different length linker arms were synthesized. The structure-activity relationship showed that the anticancer activity of TEn gradually decreased with the elongation of the linker arm. The compound TE3 has the optimal and broadest spectrum of antitumor effects. It mainly through targeting mitochondria, inducing ROS production, disrupting mitochondrial function, and activating mitochondria apoptosis pathway to exert anti-cervical cancer activity. Among them, TPP+ only acted as a mitochondrial targeting group, while EP containing peroxide bridge structure served as an active group to induce ROS. In vivo experiments have shown that TE3 has better anti-cervical cancer activity and safety than the first-line anticancer drug cisplatin, and can activate the immune response in mice. Although TE3 exhibits some acute toxicity, it is not significant at therapeutic doses. Therefore, TE3 has the potential for further development as an anti-cervical cancer drug.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.