Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
Bioorg Chem. 2022 Dec;129:106206. doi: 10.1016/j.bioorg.2022.106206. Epub 2022 Oct 17.
Heart failure is one of the diseases with the highest mortality in the world, and inflammation is the main cause for its occurrence and development. The stilbene skeleton of resveratrol has been shown to have excellent anti-inflammatory and antioxidant activities. In order to continue our research on dihydropyrazole derivatives, a series of novel (E)-4-methyl-2-(3-phenyl-5-(4-styrylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives were designed and synthesized according to the principle of molecular hybridization for evaluation their anti-inflammatory and antioxidation activities. We screened their anti-inflammatory abilities in RAW264.7 cells and analyzed the preliminary structure-activity relationship, and explored the related molecular mechanisms. We further used doxorubicin (DOX)-induced heart failure model to explore the protective role of our compound in vivo. Our results showed that compound F5 exhibited the most potent activity and was superior to the positive control. It reversed the expression of lipopolysaccharide (LPS)-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and superoxide dismutase 1 (SOD1) in RAW264.7 cells. In addition, compound F5 also inhibited DOX-induced inflammation and reactive oxygen species by modulating the p38/nuclear factor kappa B (NF-κB) signaling pathway in H9C2 cells. In vivo results showed that compound F5 ameliorated DOX-caused damage, such as reduced left ventricular ejection fraction, severe inflammation, fibrosis and oxidative stress in heart. In conclusion, compound F5 could be used as a promising agent for the treatment of heart failure through attenuating oxidative stress and inflammation.
心力衰竭是世界上死亡率最高的疾病之一，炎症是其发生和发展的主要原因。白藜芦醇的二苯乙烯骨架已被证明具有优异的抗炎和抗氧化活性。为了继续我们对二氢吡唑衍生物的研究，根据分子杂交原理设计并合成了一系列新型（E）-4-甲基-2-（3-苯基-5-（4-苯乙烯基）苯基-4,5-二氢-1H-吡唑-1-基）噻唑衍生物，以评估它们的抗炎和抗氧化活性。我们在 RAW264.7 细胞中筛选了它们的抗炎能力，并分析了初步的结构-活性关系，探讨了相关的分子机制。我们进一步使用多柔比星（DOX）诱导的心力衰竭模型在体内探索我们化合物的保护作用。结果表明，化合物 F5 表现出最强的活性，优于阳性对照。它逆转了脂多糖（LPS）调节的诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和超氧化物歧化酶 1（SOD1）在 RAW264.7 细胞中的表达。此外，化合物 F5 还通过调节 p38/核因子 kappa B（NF-κB）信号通路抑制 DOX 诱导的 H9C2 细胞炎症和活性氧。体内结果表明，化合物 F5 改善了 DOX 引起的损伤，如左心室射血分数降低、心脏严重炎症、纤维化和氧化应激。总之，化合物 F5 可通过减轻氧化应激和炎症作为心力衰竭治疗的有前途的药物。
