Novel derivatives of deoxycholic acid bearing linear aliphatic diamine and aminoalcohol moieties and their cyclic analogs at the C3 position: Synthesis and evaluation of their in vitro antitumor potential

Andrey V. Markov, Valeriya O. Babich, Irina I. Popadyuk, Oksana V. Salomatina, Evgeniya B. Logashenko, Nariman F. Salakhutdinov, Marina A. Zenkova

Результат исследования: Научные публикации в периодических изданияхстатья

Аннотация

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 (IC50 2–10 = 1.0–36.0 µM) in comparison with DCA (IC50 DCA ≥ 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.

Язык оригиналаанглийский
Номер статьи2644;
Число страниц19
ЖурналMolecules
Том24
Номер выпуска14
DOI
СостояниеОпубликовано - 21 июл 2019

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