Novel 3 '-Substituted-1 ',2 ',4 '-Oxadiazole Derivatives of 18 beta H-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

Novel 3 '-Substituted-1 ',2 ',4 '-Oxadiazole Derivatives of 18 beta H-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo Full article

Journal

International Journal of Molecular Sciences
ISSN: 1661-6596

Output data

Year: 2020, Volume: 21, Number: 10, Article number : 3511, Pages count : DOI: 10.3390/ijms21103511

Tags

18 beta H-glycyrrhetinic acid; derivatives; oxadiazole; heterocyclic moiety; antitumor activity; anti-inflammatory activity; apoptosis; metastasis; target prediction; molecular docking

Authors

Markov Andrey V. ¹ , Sen'kova Aleksandra V. ¹ , Popadyuk Irina I. ² , Salomatina Oksana V. ^1,2 , Logashenko Evgeniya B. ¹ , Komarova Nina I. ² , Ilyina Anna A. ¹ , Salakhutdinov Nariman F. ² , 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) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, Lavrentev Ave 9, Novosibirsk 630090, Russia

A series of novel 18 beta H-glycyrrhetinic acid (GA) derivatives containing 3 '-(alkyl/phenyl/pyridin(-2 '', -3 '', and -4 '')-yl)-1 ' ,2 ' ,4 ' -oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid's carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates-O-acylated amidoxime 3a-h-display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1 ' ,2 ' ,4 ' -oxadiazole analogs 4f-h (median IC50 = 7.0 and 49.7 mu M, respectively). Subsequent replacement of the 3-acetoxy group by the hydroxyl group of pyridin(-2 '', 3 '', and -4 '')-yl-1 ' ,2 ' ,4 ' -oxadiazole-bearing GA derivatives produced compounds 5f-h, showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed analysis of the antitumor activity of hit derivative 5f revealed its marked proapoptotic activity and inhibitory effects on clonogenicity and motility of HeLa cervical carcinoma cells in vitro, and the metastatic growth of B16 melanoma in vivo. Additionally, the comprehensive in silico study revealed intermediate 3d, bearing the tert-butyl moiety in O-acylated amidoxime, as a potent anti-inflammatory candidate, which was able to effectively inhibit inflammatory response induced by IFN gamma in macrophages in vitro and carrageenan in murine models in vivo, probably by primary interactions with active sites of MMP9, neutrophil elastase, and thrombin. Taken together, our findings provide a basis for a better understanding of the structure-activity relationship of 1 ' ,2 ' ,4 ' -oxadiazole-containing triterpenoids and reveal two hit molecules with pronounced antitumor (5f) and anti-inflammatory (3d) activities.

Markov A.V. , Sen'kova A.V. , Popadyuk I.I. , Salomatina O.V. , Logashenko E.B. , Komarova N.I. , Ilyina A.A. , Salakhutdinov N.F. , Zenkova M.A.
Novel 3 '-Substituted-1 ',2 ',4 '-Oxadiazole Derivatives of 18 beta H-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

International Journal of Molecular Sciences. 2020. V.21. N10. 3511 . DOI: 10.3390/ijms21103511 WOS Scopus РИНЦ OpenAlex

Full text from publisher

Published online:

May 15, 2020

Web of science:	WOS:000539312100107
Scopus:	2-s2.0-85084963794
Elibrary:	43304578
OpenAlex:	W3024821363

DB	Citing
Web of science	11
Scopus	12
Elibrary	10
OpenAlex	14