Institute of Medical Biology, Polish Academy of Sciences, Łódź, Poland.
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2171028. doi: 10.1080/14756366.2023.2171028.
The synthesis of carborane-1,8-naphthalimide conjugates and evaluation of their DNA-binding ability and anticancer activity were performed. A series of 4-carboranyl-3-nitro-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, were synthesised via amidation and reductive amination reactions, and their calf thymus DNA (ct-DNA)-binding properties were investigated using circular dichroism, UV-vis spectroscopy, and thermal denaturation. Results showed that conjugates - interacted very strongly with ct-DNA (Δ = 10.00-13.00 °C), indicating their ability to intercalate with DNA, but did not inhibit the activity of topoisomerase II. The conjugates inhibited the cell growth of the HepG2 cancer cell line . The same compounds caused the G2M phase arrest. Cell lines treated with these conjugates showed an increase in reactive oxygen species, glutathione, and Fe levels, lipid peroxidation, and mitochondrial membrane potential relative to controls, indicating the involvement of ferroptosis. Furthermore, these conjugates caused lysosomal membrane permeabilization in HepG2 cells but not in MRC-5 cells.
合成了碳硼烷-1,8-萘酰亚胺缀合物，并评价了它们与 DNA 的结合能力和抗癌活性。通过酰胺化和还原胺化反应合成了一系列 4-碳硼烷-3-硝基-1,8-萘酰亚胺衍生物，米托萘胺和皮那非德类似物，并使用圆二色性、紫外可见光谱和热变性研究了它们与小牛胸腺 DNA（ct-DNA）的结合特性。结果表明，缀合物与 ct-DNA 相互作用非常强（Δ=10.00-13.00°C），表明它们能够与 DNA 嵌入，但不抑制拓扑异构酶 II 的活性。这些缀合物抑制了 HepG2 癌细胞系的细胞生长。相同的化合物导致 G2M 期阻滞。与对照组相比，用这些缀合物处理的细胞系中活性氧、谷胱甘肽和 Fe 水平、脂质过氧化和线粒体膜电位增加，表明铁死亡的参与。此外，这些缀合物导致 HepG2 细胞中的溶酶体膜通透性增加，但在 MRC-5 细胞中没有。
