Background: 1,2,3,4,5-pentathiepines (PTEs) are compounds originally identified in marine ascidians and are currently under investigation for their promising pharmacological properties, particularly as potential antineoplastic agents. Objectives: In this study, we investigated the antineoplastic properties of a series of ten indolizine-based PTEs, comprising eight previously reported compounds and two newly synthesized derivatives. Methods: These compounds were evaluated against a panel of human cancer cell lines of diverse tissue origins, as well as, for the first time, on non-cancerous CR9 fibroblasts to assess their cytotoxic selectivity. In addition, their effects were tested on 3D spheroid models, providing preliminary insights into their potential in vivo efficacy. Initial screening focused on cell viability, followed by a more detailed characterization of the most active compounds in terms of their ability to induce apoptosis, necrosis, cell cycle arrest, and reactive oxygen species (ROS) generation. The anti-migratory activity of PTEs and a newly adapted assay to confirm sulfur species release in the cells were also performed for the first time. Results and Conclusions: Our findings reveal that four PTEs bearing hydrophilic, hydrogen-bonding functional groups, particularly the two inspired by natural analogs, exhibited the most potent anticancer activity.
背景：1,2,3,4,5-五硫杂环庚烷（PTEs）是最初在海鞘类海洋生物中发现的化合物，目前因其具有前景的药理特性（尤其是作为潜在的抗肿瘤药物）而受到研究关注。目的：本研究探讨了十种基于吲哚嗪结构的PTEs的抗肿瘤特性，其中包括八种已报道化合物及两种新合成的衍生物。方法：通过多种组织来源的人类癌细胞系对这些化合物进行评估，并首次在非癌性CR9成纤维细胞上测试其细胞毒性选择性。此外，还在三维球体模型中检测了它们的作用，从而初步评估其潜在的体内疗效。初步筛选聚焦于细胞活力，随后对活性最强的化合物进行了更详细的表征，包括其诱导细胞凋亡、坏死、细胞周期阻滞及活性氧生成的能力。研究还首次评估了PTEs的抗迁移活性，并采用新建立的检测方法验证了其在细胞内释放硫物种的过程。结果与结论：研究结果表明，四种带有亲水性氢键官能团的PTEs（特别是两种受天然类似物启发合成的化合物）表现出最强的抗癌活性。
Anticancer Effect of Nature-Inspired Indolizine-Based Pentathiepines in 2D and 3D Cellular Model
肿瘤(癌症)患者之家