State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
J Med Chem. 2024 Aug 22;67(16):14234-14255. doi: 10.1021/acs.jmedchem.4c01099. Epub 2024 Aug 13.
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 () and 40 simplifiers () were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of . Among these compounds, showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) and , and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that promoted the efflux of cisplatin 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. 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.
顺铂是一种广泛用于肿瘤临床治疗的药物。然而，其肾毒性限制了它的广泛应用。基于 Psiguamer A 和 B 的全合成，我们合成了一系列化合物，包括 8 个类似物 () 和 40 个简化物 ()，它们是来自 的新型倍半萜类化合物，具有不寻常的骨架。在这些化合物中， 对顺铂诱导的急性肾损伤 (AKI) 表现出最强的保护作用， ，并略微增强了顺铂的抗肿瘤功效。机制研究表明， 通过上调铜转运外排蛋白 ATP7A 和 ATP7B 促进顺铂的外排。它通过激活单磷酸腺苷激活的蛋白激酶 (AMPK) 信号通路增强自噬。 在 1 g/kg 的单剂量下，在健康小鼠中没有表现出急性毒性或明显的病理损伤。这项研究为对抗顺铂诱导的 AKI 提供了一个有前途的先导化合物。
