School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
Department of Emergency and Minimally Invasive Surgery, The Third Affiliated Hospital of Anhui Medical University, The First People's Hospital of Hefei, Binhu Hospital District, Hefei, China.
Clin Exp Pharmacol Physiol. 2022 Aug;49(8):824-835. doi: 10.1111/1440-1681.13670. Epub 2022 Jun 23.
Necroptosis, a form of inflammation-related programmed cell death, is a major mechanism of proximal tubular cell injury in acute kidney injury (AKI). Blockade of necroptosis signalling represents a promising strategy for clinical therapy of AKI. Previously, we identified a small molecular receptor-interacting protein kinases (RIPK)1 inhibitor Cpd-71 with nephroprotective activities. To discover more nephroprotective agents, in this study, 20 chalcone derivatives were synthesized and evaluated for their anti-necroptosis and nephroprotective activities. Among the chalcone derivatives, Cpd-2 exhibited the most potent anti-necroptosis activity (IC = 1.08 μM) and protective activity (EC = 1.49 μM) through directly binding to RIPK1 and blocking RIPK1-RIPK3-mixed-lineage kinase domain-like protein (MLKL) signalling pathway. Furthermore, Cpd-2 effectively attenuated cisplatin or hypoxia/reoxygenation (H/R)-induced injury and necroptotic inflammation in renal cell models. Moreover, in cisplatin- or ischemia/reperfusion (I/R) induced AKI mouse model, detection of creatinine and urea nitrogen in blood showed that Cpd-2 improved kidney function. Periodic acid-Schiff (PAS) staining and immunofluorescence analysis indicated that Cpd-2 also reduced pathological damage and inhibited inflammatory development in kidney tissues. In summary, although some chalcone derivatives have been reported to prevent kidney injury previously, our present study not only discovered a promising leading compound Cpd-2, but also provided a novel and successful practice for the development of necroptosis inhibitors from natural products derivatives as AKI therapeutic agents.
细胞坏死，一种炎症相关的程序性细胞死亡形式，是急性肾损伤（AKI）中近端肾小管细胞损伤的主要机制。阻断细胞坏死信号代表了 AKI 临床治疗的一种有前途的策略。先前，我们鉴定了一种具有肾脏保护活性的小分子受体相互作用蛋白激酶（RIPK）1 抑制剂 Cpd-71。为了发现更多的肾脏保护剂，在这项研究中，我们合成了 20 种查尔酮衍生物，并评估了它们的抗细胞坏死和肾脏保护活性。在查尔酮衍生物中，Cp d-2 通过直接与 RIPK1 结合并阻断 RIPK1-RIPK3-混合谱系激酶结构域样蛋白（MLKL）信号通路，表现出最强的抗细胞坏死活性（IC = 1.08 μM）和保护活性（EC = 1.49 μM）。此外，Cp d-2 有效减轻顺铂或缺氧/复氧（H/R）诱导的肾细胞模型损伤和细胞坏死性炎症。此外，在顺铂或缺血/再灌注（I/R）诱导的 AKI 小鼠模型中，血液中肌酐和尿素氮的检测表明 Cpd-2 改善了肾功能。过碘酸希夫（PAS）染色和免疫荧光分析表明，Cp d-2 还减少了肾脏组织中的病理损伤并抑制了炎症的发展。总之，尽管先前已有一些查尔酮衍生物被报道可预防肾损伤，但我们的研究不仅发现了一种有前途的先导化合物 Cpd-2，还为从天然产物衍生物开发细胞坏死抑制剂作为 AKI 治疗剂提供了一种新的成功实践。
