Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent'ev ave., 8, 630090 Novosibirsk, Russia.
Novosibirsk State University, Pirogova str. 2, 630090 Novosibirsk, Russia.
Molecules. 2019 Jul 21;24(14):2644. doi: 10.3390/molecules24142644.
A series of novel deoxycholic acid (DCA) derivatives containing aliphatic diamine and aminoalcohol or morpholine moieties at the C3 position were synthesized by 3,26-epoxide ring-opening reactions. These compounds were investigated for their cytotoxicity in four human tumor cell lines and murine macrophages and for inhibitory activity against macrophage-mediated NO synthesis in vitro. Obtained data revealed that: (i) all amine-containing substituents significantly increased the cytotoxicity of the novel compounds (IC = 1.0-36.0 μM) in comparison with DCA (IC ≥ 82.9 μM); (ii) aminoalcohol moieties were more preferable than diamine moieties due to the fact they imparted better selectivity for tumor cells of the novel derivatives; (iii) the susceptibility of tested cell lines to derivatives diminished in the following order: HuTu-80 (duodenal carcinoma) ≈ HepG2 (hepatocarcinoma) > KB-3-1 (cervical carcinoma) > RAW264.7 (macrophages) > A549 (lung carcinoma); (iv) compounds and , bearing aminoethanol and aminopropanol moieties, respectively, exhibited high cytotoxic selectivity indexes (SI = 7.9 and 8.3, respectively) and good drug-likeness parameters; (v) the novel compounds do not display anti-NO activity. Mechanistic study revealed that compound induces ROS-dependent cell death by activation of intrinsic caspase-dependent apoptosis and cytodestructive autophagy in HuTu-80 cells and vitamin D receptor can be considered as its primary target.
一系列新型的脱氧胆酸（DCA）衍生物通过 3,26-环氧化物开环反应，在 C3 位上含有脂肪族二胺和氨醇或吗啉部分。这些化合物在四种人肿瘤细胞系和小鼠巨噬细胞中进行了细胞毒性测试，并在体外抑制了巨噬细胞介导的一氧化氮合成的活性。研究结果表明：（i）与 DCA（IC≥82.9μM）相比，所有含胺取代基的化合物（IC=1.0-36.0μM）都显著增加了新型化合物的细胞毒性；（ii）与二胺取代基相比，氨醇取代基更具优势，因为它们赋予了新型衍生物对肿瘤细胞更好的选择性；（iii）测试细胞系对衍生物的敏感性按以下顺序递减：HuTu-80（十二指肠癌）≈HepG2（肝癌）>KB-3-1（宫颈癌）>RAW264.7（巨噬细胞）>A549（肺癌）；（iv）分别含有氨基乙醇和氨基丙醇取代基的化合物和，表现出高的细胞毒性选择性指数（SI=7.9 和 8.3）和良好的药物相似性参数；（v）新型化合物没有抗-NO 活性。机制研究表明，化合物通过激活内在的 caspase 依赖性细胞凋亡和细胞破坏性自噬，在 HuTu-80 细胞中诱导 ROS 依赖性细胞死亡，维生素 D 受体可以被认为是其主要靶点。
