Abstract
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 (IC502–10 = 1.0–36.0 μM) in comparison with DCA (IC50DCA ≥ 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 8 and 9, bearing aminoethanol and aminopropanol moieties, respectively, exhibited high cytotoxic selectivity indexes (SIHuTu-80 = 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 9 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.
Highlights
Bile acids (BAs)—steroidal molecules synthesized in the liver of mammals—are essential for the absorption of dietary lipids and liposoluble vitamins
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 ≈ HepG2 > KB-3-1 > RAW264.7 > A549; (iv) compounds 8 and 9, bearing aminoethanol and aminopropanol moieties, respectively, exhibited high cytotoxic selectivity indexes (SIHuTu-80 = 7.9 and 8.3, respectively) and good drug-likeness parameters; (v) the novel compounds do not display anti-Nitric oxide (NO) activity
In order to analyze the influence of the replacement of the terminal amino groups within the diamine moieties by oxygen-containing groups on bioactivity of deoxycholic acid (DCA) derivatives, 2-aminoethanol, 3-aminopropanol and morpholine were taken for synthesis
Summary
Bile acids (BAs)—steroidal molecules synthesized in the liver of mammals—are essential for the absorption of dietary lipids and liposoluble vitamins. In a view of the fact that BAs, as well as other natural metabolites, display a wide spectrum of bioactivities based on their multitarget mode of action, these compounds have been the subject of numerous pharmacological studies [1,2]. Along with the diamine substituents, the nitrogen-containing moieties with other heteroatoms are considered as attractive connecting units—the BA derivatives bearing them display diverse pharmacological effects. BA sulphonamides and cholic acid derivatives, containing amino acid or triazolyl fragments, show pronounced carbonic anhydrase inhibitory and anti-tuberculosis activities, respectively [16,17]. The particular attention of researchers in this field is attracted to aminoalcohol moieties—it was shown that introduction of such fragments in BA molecules enhanced antifungal and lipid reducing activities [18,19] and improved gel-forming properties [20]. To the best of our knowledge, the anti-proliferative effects of aminoalcohol-containing BA derivatives have not been yet investigated
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