Synthesis and Biological Evaluation of Novel <i>Psidium</i> Meroterpenoid Derivatives against Cisplatin-Induced Acute Kidney Injury

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 (<b>G3-G10</b>) and 40 simplifiers (<b>G11-G50</b>) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of <i>Psidium guajava</i>. Among these compounds, <b>(</b><i><b>d</b></i><b>)-G8</b> showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) <i>in vitro</i> and <i>vivo</i>, and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that <b>(</b><i><b>d</b></i><b>)-G8</b> promoted the efflux of cisplatin <i>via</i> 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. <b>(</b><i><b>d</b></i><b>)-G8</b> 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.