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 Full article
Journal |
Molecules
, E-ISSN: 1420-3049 |
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Output data | Year: 2019, Volume: 24, Number: 14, Article number : 2644, Pages count : DOI: 10.3390/molecules24142644 | ||||||
Tags | deoxycholic acid derivatives; diamines; aminoalcohols; apoptosis; autophagy; VDR | ||||||
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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 mu M) in comparison with DCA (IC50DCA >= 82.9 mu M); (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) approximate to 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.
Cite:
Markov A.V.
, Babich V.O.
, Popadyuk I.I.
, Salomatina O.V.
, Logashenko E.B.
, Salakhutdinov N.F.
, Zenkova M.A.
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
Molecules. 2019. V.24. N14. 2644 . DOI: 10.3390/molecules24142644 WOS Scopus РИНЦ
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
Molecules. 2019. V.24. N14. 2644 . DOI: 10.3390/molecules24142644 WOS Scopus РИНЦ
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Full text from publisher
Dates:
Published online: | Jul 21, 2019 |
Identifiers:
Web of science | WOS:000482303000127 |
Scopus | 2-s2.0-85069672130 |
Elibrary | 41615813 |
OpenAlex | W2963950227 |