Sen'kova Aleksandra V, Savin Innokenty A, Odarenko Kirill V, Salomatina Oksana V, Salakhutdinov Nariman F, Zenkova Marina A, Markov Andrey V
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent'ev avenue, 8, 630090 Novosibirsk, Russia.
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrent'ev avenue, 9, 630090 Novosibirsk, Russia.
Biomed Pharmacother. 2023 Mar;159:114231. doi: 10.1016/j.biopha.2023.114231. Epub 2023 Jan 12.
The anti-inflammatory potential of three cyanoenone-containing triterpenoids, including soloxolone methyl (SM), soloxolone (S) and its novel derivative bearing at the C-30 amidoxime moiety (SAO), was studied in murine models of acute inflammation. It was found that the compounds effectively suppressed the development of carrageenan-induced paw edema and peritonitis as well as lipopolysaccharide (LPS)-driven acute lung injury (ALI) with therapeutic outcomes comparable with that of the reference drugs indomethacin and dexamethasone. Non-immunogenic carrageenan-stimulated inflammation was more sensitive to the transformation of C-30 of SM compared with immunogenic LPS-induced inflammation: the anti-inflammatory properties of the studied compounds against carrageenan-induced paw edema and peritonitis decreased in the order of SAO > S > > SM, whereas the efficiency of these triterpenoids against LPS-driven ALI was similar (SAO ≈ S ≈ SM). Further studies demonstrated that soloxolone derivatives significantly inhibited a range of immune-related processes, including granulocyte influx and the expression of key pro-inflammatory cytokines and chemokines in the inflamed sites as well as the functional activity of macrophages. Moreover, SM was found to prevent inflammation-associated apoptosis of A549 pneumocytes and effectively inhibited the protease activity of thrombin (IC = 10.3 µM) tightly associated with rodent inflammatome. Taken together, our findings demonstrate that soloxolone derivatives can be considered as novel promising anti-inflammatory drug candidates with multi-targeted mechanism of action.
在急性炎症的小鼠模型中，研究了三种含氰基烯酮的三萜类化合物的抗炎潜力，其中包括甲基索罗索龙（SM）、索罗索龙（S）及其在C-30位带有偕胺肟部分的新型衍生物（SAO）。结果发现，这些化合物能有效抑制角叉菜胶诱导的爪肿胀和腹膜炎以及脂多糖（LPS）引发的急性肺损伤（ALI），治疗效果与参比药物吲哚美辛和地塞米松相当。与免疫原性LPS诱导的炎症相比，非免疫原性角叉菜胶刺激的炎症对SM的C-30转化更敏感：所研究化合物对角叉菜胶诱导的爪肿胀和腹膜炎抗炎特性的降低顺序为SAO > S > > SM，而这些三萜类化合物对LPS驱动的ALI的疗效相似（SAO ≈ S ≈ SM）。进一步研究表明，索罗索龙衍生物能显著抑制一系列免疫相关过程，包括粒细胞流入以及炎症部位关键促炎细胞因子和趋化因子的表达，还有巨噬细胞的功能活性。此外，发现SM可预防A549肺细胞与炎症相关的凋亡，并有效抑制与啮齿动物炎性小体紧密相关的凝血酶的蛋白酶活性（IC = 10.3 μM）。综上所述，我们的研究结果表明，索罗索龙衍生物可被视为具有多靶点作用机制的新型有前景的抗炎候选药物。
