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Synthesis and Biological Evaluation of Novel Psidium Meroterpenoid Derivatives against Cisplatin-Induced Acute Kidney Injury
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jmedchem.4c01099 Ying-Da Zang 1 , Hai-Jie Wu 1 , Xin-Yi Chen 1 , Zhi-Ling Ma 1 , Chuang-Jun Li 1 , Jie Ma 1 , Xiao-Guang Chen 1 , Li Sheng 1 , Sen Zhang 1 , Dong-Ming Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jmedchem.4c01099 Ying-Da Zang 1 , Hai-Jie Wu 1 , Xin-Yi Chen 1 , Zhi-Ling Ma 1 , Chuang-Jun Li 1 , Jie Ma 1 , Xiao-Guang Chen 1 , Li Sheng 1 , Sen Zhang 1 , Dong-Ming Zhang 1
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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.
中文翻译：
新型银子类萜类衍生物的合成及抗顺铂急性肾损伤的生物学评价
顺铂是临床广泛应用的肿瘤治疗药物。然而，肾毒性限制了其广泛使用。在Psiguamer A和B的全合成基础上，合成了一系列化合物，包括8个类似物( G3-G10 )和40个简化物( G11-G50 )，Psiguamer A和B是来自Psidium guajava叶子的具有独特骨架的新型半萜类化合物。其中， ( d )-G8对顺铂引起的急性肾损伤(AKI)的体外和体内保护作用最强，并略微增强顺铂的抗肿瘤功效。机制研究表明， ( d )-G8通过上调铜转运外排蛋白 ATP7A 和 ATP7B 来促进顺铂的外排。它通过激活单磷酸腺苷激活蛋白激酶（AMPK）信号通路来增强自噬。 ( d )-G8在健康小鼠中单剂量1g/kg时未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 提供了有希望的线索。
更新日期：2024-08-13
中文翻译：
新型银子类萜类衍生物的合成及抗顺铂急性肾损伤的生物学评价
顺铂是临床广泛应用的肿瘤治疗药物。然而，肾毒性限制了其广泛使用。在Psiguamer A和B的全合成基础上，合成了一系列化合物，包括8个类似物( G3-G10 )和40个简化物( G11-G50 )，Psiguamer A和B是来自Psidium guajava叶子的具有独特骨架的新型半萜类化合物。其中， ( d )-G8对顺铂引起的急性肾损伤(AKI)的体外和体内保护作用最强，并略微增强顺铂的抗肿瘤功效。机制研究表明， ( d )-G8通过上调铜转运外排蛋白 ATP7A 和 ATP7B 来促进顺铂的外排。它通过激活单磷酸腺苷激活蛋白激酶（AMPK）信号通路来增强自噬。 ( d )-G8在健康小鼠中单剂量1g/kg时未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 提供了有希望的线索。
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