Trioxolone Methyl, a Novel Cyano Enone-Bearing 18βH-Glycyrrhetinic Acid Derivative, Ameliorates Dextran Sulphate Sodium-Induced Colitis in Mice.

Andrey V Markov,Nariman F Salakhutdinov,Oksana V Salomatina,Marina A Zenkova,Dina V Korchagina,Aleksandra V Sen’Kova,Evgeniya B Logashenko

doi:10.3390/molecules25102406

Abstract

Semi-synthetic triterpenoids, bearing cyano enone functionality in ring A, are considered to be novel promising therapeutic agents with complex inhibitory effects on tissue damage, inflammation and tumor growth. Previously, we showed that the cyano enone-containing 18βH-glycyrrhetinic acid derivative soloxolone methyl (SM) effectively suppressed the inflammatory response of macrophages in vitro and the development of influenza A-induced pneumonia and phlogogen-stimulated paw edema in vivo. In this work, we reported the synthesis of a novel 18βH-glycyrrhetinic acid derivative trioxolone methyl (TM), bearing a 2-cyano-3-oxo-1(2)-en moiety in ring A and a 12,19-dioxo-9(11),13(18)-dien moiety in rings C, D, and E. TM exhibited a high inhibitory effect on nitric oxide (II) production by lipopolysaccharide-stimulated J774 macrophages in vitro and dextran sulfate sodium (DSS)-induced colitis in mice, displaying higher anti-inflammatory activity in comparison with SM. TM effectively suppressed the DSS-induced epithelial damage and inflammatory infiltration of colon tissue, the hyperproduction of colonic neutral mucin and TNFα and increased glutathione synthesis. Our in silico analysis showed that Akt1, STAT3 and dopamine receptor D2 can be considered as mediators of the anti-colitic activity of TM. Our findings provided valuable information for a better understanding of the anti-inflammatory activity of cyano enone-bearing triterpenoids and revealed TM as a promising anti-inflammatory candidate.

Highlights

Michael acceptor groups are important structural elements of a broad range of pharmacologically active compounds, as they determine the direct interaction with biologically relevant targets
We found that the anti-inflammatory activity of TMofwas (DSS)-induced colitis in mice in vivo
We showed the ability of soloxolone methyl (SM) to form a hydrogen bond with Arg609 (3.03 Å), which was crucial for the development of STAT3 inhibitors [39,40], whereas in the case of other proteins, SM did not interact with functionally important residues or formed significantly less hydrophobic bonds compared to trioxolone methyl (TM); see the DRD2–SM complex as an example (Figure 6D)

Summary

Introduction

Michael acceptor groups are important structural elements of a broad range of pharmacologically active compounds, as they determine the direct interaction with biologically relevant targets. Cysteine thiol groups of proteins are considered one of the most susceptible sites to Michael acceptor additions, and the formation of thiol adducts with proteins underpins a high biological activity and a multi-targeted mode of action of Michael acceptor-bearing agents [1]. One of the most studied Michael acceptor pharmacophore groups is the α-cyano α,β-unsaturated carbonyl moiety. The formation of an additional Michael acceptor center at C-9 by creating the 12-oxo-9(11)-en moiety in the C ring of the triterpenoid scaffold along with the 2-cyano-3-oxo-1(2)-en system. Molecules 2020, 25, 2406 significantly enhanced the bioactivity of semi-synthetic triterpenoids (Figure 1) [9,10,11,12].

Methods

Discussion

Conclusion