N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Academician Lavrent'ev Ave. 9, 630090 Novosibirsk, Russian Federation.
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Academician Lavrent'ev Ave. 9, 630090 Novosibirsk, Russian Federation.
Steroids. 2022 Aug;184:109042. doi: 10.1016/j.steroids.2022.109042. Epub 2022 May 14.
Semisynthetic triterpenoid betulonic acid is of significant interest due to its biological activity and synthetic application. In this study, we report the synthesis of hybrid compounds, containing betulonic acid carboxamide and arylpyrimidine fragments. A total of 15 conjugates were prepared using the cyclocondensation reaction of new terpenoid alkynyl ketones with amidinium salts. The main synthetic approach to betulonic acid amide-derived alkynylketones was based on the cross-coupling reaction of N-(4-ethynylphenyl)- or N-(2-(4-ethynylphenyl)-1-(methoxycarbonyl)ethyl)- substituted betulonic acid carboxamide with aroylchlorides. Cyclocondensation of alkynones with amidine or guanidine hydrochlorides by reflux in MeCN in the presence of KCO led to the formation of terpenoid pyrimidine hybrids in 52-89% isolated yield. Anti-inflammatory properties of new type of triterpenoid-pyrimidine conjugates were studied using the histamine- and concanavalin A- induced mouse paw edema models. In a model of acute inflammation betulonic acid amide-arylpyrimidines containing a 4-fluorophenyl substituent at the C-6 position of pyrimidine ring exhibited significant and selective anti-inflammatory activity. Compounds containing the 4-bromophenyl- substituent in the pyrimidine ring revealed selective anti-inflammatory activity in the model of immunogenic inflammation (concanavalin-A model). It should be noted that the methoxycarbonyl substituted ethane link between pharmacophore ligands (betulonic acid carboxamide and arylpyrimidine) has a significant effect on anti-inflammatory activity in both in vivo models of inflammation. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their pyrimidine substituent with the formation of more non-covalent bonds.
由于其生物活性和合成应用，半合成三萜类化合物桦木酸酰胺引起了人们的极大关注。在本研究中，我们报告了含有桦木酸酰胺和芳基嘧啶片段的杂合化合物的合成。使用新型萜烯炔基酮与脒盐的环缩合反应，共制备了 15 个缀合物。桦木酸酰胺衍生的炔基酮的主要合成方法基于 N-(4-乙炔基苯基)-或 N-(2-(4-乙炔基苯基)-1-(甲氧羰基)乙基)-取代桦木酸酰胺与芳酰氯的交叉偶联反应。在 MeCN 中回流，在 KCO 的存在下，将炔酮与脒或胍盐酸盐环缩合，以 52-89%的分离产率形成萜类嘧啶杂合体。使用组胺和刀豆蛋白 A 诱导的小鼠爪肿胀模型研究了新型三萜-嘧啶缀合物的抗炎特性。在急性炎症模型中，含有嘧啶环上 6 位 4-氟苯基取代基的桦木酸酰胺-芳基嘧啶表现出显著的选择性抗炎活性。在免疫性炎症模型（刀豆蛋白 A 模型）中，含有嘧啶环上 4-溴苯基取代基的化合物显示出选择性抗炎活性。应当指出，药效团配体（桦木酸酰胺和芳基嘧啶）之间的甲氧羰基取代的乙烷键对两种炎症体内模型的抗炎活性均有重要影响。分子对接表明，新衍生物通过嘧啶取代基与 Keap1 Kelch 结构域的结合位点结合，形成更多的非共价键。
