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

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

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

Authors

Markov Andrey V. ¹ , Babich Valeriya O. ^1,2 , Popadyuk Irina I. ³ , Salomatina Oksana V. ^1,3 , Logashenko Evgeniya B. ¹ , Salakhutdinov Nariman F. ^2,3 , Zenkova Marina A. ¹

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, Lavrentev Ave 8, Novosibirsk 630090, Russia
2	(Данные Web of science) Novosibirsk State Univ, Pirogova Str 2, Novosibirsk 630090, Russia
3	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, Lavrentev Ave 9, Novosibirsk 630090, Russia

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.

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 OpenAlex

Full text from publisher

Published online:

Jul 21, 2019

Web of science:	WOS:000482303000127
Scopus:	2-s2.0-85069672130
Elibrary:	41615813
OpenAlex:	W2963950227

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