Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Universität Greifswald, 17489 Greifswald, Germany.
Bioanorganische Chemie, Institut für Biochemie, Universität Greifswald, 17489 Greifswald, Germany.
Int J Mol Sci. 2021 Jul 16;22(14):7631. doi: 10.3390/ijms22147631.
Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.
戊噻嗪是一种含多硫的化合物，对癌细胞具有抗增殖和细胞毒性作用，诱导氧化应激和细胞凋亡，并抑制谷胱甘肽过氧化物酶 (GPx1)。这使得它们成为有前途的抗癌药物开发候选物。然而，它们在不同的癌细胞系中的生物效应及其相互作用尚未得到系统评估。在这项研究中，合成了六种新型戊噻嗪以满足特定要求，如荧光特性或提高水溶性。通过 X 射线晶体学成功阐明了三种衍生物的结构。所有六种化合物都在 14 个人类癌细胞系中进行了广泛的生物学评估。这些研究包括调查对 GPx1 和细胞增殖、细胞毒性以及 ROS 和 DNA 链断裂的诱导的抑制作用。此外，还研究了选定的细胞凋亡标志和对细胞周期进程的影响。所有六种戊噻嗪都表现出高细胞毒性和抗增殖活性，而其中五种还强烈抑制了 GPx1。在以单链和双链断裂形式引起氧化应激和 DNA 损伤之间存在明显的联系。此外，这些研究支持凋亡而不是铁死亡作为一些细胞系中细胞死亡的机制。由于各种戊噻嗪产生不同的生物学反应，因此生物效应的调节取决于融合到硫环上的不同化学结构。这可能允许将来优化戊噻嗪的抗癌活性。
