Synthesis and Biological Evaluation of Novel Psidium Meroterpenoid Derivatives against Cisplatin-Induced Acute Kidney Injury.
Ying-Da ZangHai-Jie WuXin-Yi ChenZhi-Ling MaChuang-Jun LiJie MaXiao-Guang ChenLi ShengYonghong FuDong-Ming ZhangPublished in: Journal of medicinal chemistry (2024)
Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs ( G3-G10 ) and 40 simplifiers ( G11-G50 ) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava . Among these compounds, ( d )-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo , and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that ( d )-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. ( d )-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.
Keyphrases
- acute kidney injury
- signaling pathway
- cardiac surgery
- protein kinase
- oxidative stress
- skeletal muscle
- magnetic resonance imaging
- cell death
- epithelial mesenchymal transition
- type diabetes
- liver failure
- adipose tissue
- magnetic resonance
- computed tomography
- pi k akt
- intensive care unit
- metabolic syndrome
- insulin resistance
- high fat diet induced
- diffusion weighted imaging
- adverse drug
- extracorporeal membrane oxygenation
- wild type
- mechanical ventilation