Wang Ziqing, Mu Wenwen, Li Pengxiao, Liu Guoyun, Yang Jie
School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China.
School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China.
Eur J Pharm Sci. 2021 May 1;160:105756. doi: 10.1016/j.ejps.2021.105756. Epub 2021 Feb 12.
Curcumin was reported as an anti-inflammatory agent. However, curcumin's poor bioavailability limited its clinical utility. Here, thirty ortho-substituted mono-carbonyl curcumin derivatives, containing acetone, cyclopentanone, cyclohexanone or 4-piperidione (NH, N-methyl or N-acrylyl) moieties replacing β-diketone moiety of curcumin, were investigated for anti-inflammatory activity. Two active ortho-trifluoromethoxy-substituted 4-piperidione-containing derivatives 22 and 24 owned good cell uptake ability, and displayed excellent anti-inflammatory activity in both lipopolysaccharide-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. They inhibited the production of nitric oxide, reactive oxygen species, malonic dialdehyde and cyclooxygenase-2; and the expression of pro-inflammatory cytokines interleukin-1β, tumor necrosis factor-α and myeloperoxidase; the phosphorylation of mitogen-activated protein kinases; and the nucleus translocation of p65. What's more, 22 or 24 oral administered reduced the severity of clinical symptoms of ulcerative colitis (body weight and disease activity index), and reduced obviously DSS-induced colonic pathological damage (the colon length and histopathology analysis). These results suggested that ortho-trifluoromethoxy-substituted 4-piperidione-containing mono-carbonyl curcumin derivatives 22 and 24 were potential anti-inflammatory agents; and offered the important information for design and discovery of more potent anti-inflammatory drug candidates.
姜黄素被报道为一种抗炎剂。然而，姜黄素较差的生物利用度限制了其临床应用。在此，研究了三十种邻位取代的单羰基姜黄素衍生物，它们含有丙酮、环戊酮、环己酮或4-哌啶酮（NH、N-甲基或N-丙烯酰基）部分取代姜黄素的β-二酮部分，以考察其抗炎活性。两种具有活性的邻位三氟甲氧基取代的含4-哌啶酮衍生物22和24具有良好的细胞摄取能力，并且在脂多糖诱导的Raw264.7巨噬细胞和葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中均表现出优异的抗炎活性。它们抑制一氧化氮、活性氧、丙二醛和环氧合酶-2的产生；抑制促炎细胞因子白细胞介素-1β、肿瘤坏死因子-α和髓过氧化物酶的表达；抑制丝裂原活化蛋白激酶的磷酸化；以及p65的核转位。此外，口服22或24可减轻溃疡性结肠炎的临床症状严重程度（体重和疾病活动指数），并明显减轻DSS诱导的结肠病理损伤（结肠长度和组织病理学分析）。这些结果表明，邻位三氟甲氧基取代的含4-哌啶酮单羰基姜黄素衍生物22和24是潜在的抗炎剂；并为设计和发现更有效的抗炎候选药物提供了重要信息。
