TY - JOUR

T1 - Novel derivatives of deoxycholic acid bearing linear aliphatic diamine and aminoalcohol moieties and their cyclic analogs at the C3 position

T2 - Synthesis and evaluation of their in vitro antitumor potential

AU - Markov, Andrey V.

AU - Babich, Valeriya O.

AU - Popadyuk, Irina I.

AU - Salomatina, Oksana V.

AU - Logashenko, Evgeniya B.

AU - Salakhutdinov, Nariman F.

AU - Zenkova, Marina A.

PY - 2019/7/21

Y1 - 2019/7/21

N2 - 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.

AB - 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.

KW - Aminoalcohols

KW - Apoptosis

KW - Autophagy

KW - Deoxycholic acid derivatives

KW - Diamines

KW - VDR

KW - PATHWAYS

KW - APOPTOSIS

KW - aminoalcohols

KW - autophagy

KW - deoxycholic acid derivatives

KW - apoptosis

KW - AUTOPHAGY

KW - INDUCTION

KW - CANCER

KW - DISCOVERY

KW - CELL-DEATH

KW - BILE-ACIDS

KW - diamines

KW - CARBONIC-ANHYDRASE INHIBITORS

UR - http://www.scopus.com/inward/record.url?scp=85069672130&partnerID=8YFLogxK

U2 - 10.3390/molecules24142644

DO - 10.3390/molecules24142644

M3 - Article

C2 - 31330911

AN - SCOPUS:85069672130

VL - 24

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 14

M1 - 2644;

ER -