New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation,Chemical Research in Toxicology

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New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-11-24 , DOI: 10.1021/acs.chemrestox.1c00347
Nalin Singh ₁ , Anders Vik ₂ , Daniel B Lybrand ₁ , Christophe Morisseau ₁ , Bruce D Hammock ₁

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The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.

中文翻译：

环氧二十碳三烯酸的新型烷氧基类似物通过减少线粒体功能障碍、氧化应激、丝裂原激活的蛋白激酶信号传导和半胱天冬酶激活来减轻顺铂的体外肾毒性

顺铂是一种高效的化疗药物，但其严重的肾毒性限制了其使用。花生四烯酸（ARA）衍生的环氧二十碳三烯酸（EET）和可溶性环氧化物水解酶（sEH）抑制剂被证明可以改善这种剂量限制性副作用，但这两种方法都有一些药理学局限性。 EET 类似物是一种具有独特优势的替代途径，但当前的一系列类似物面临着对其结构和模拟功能的担忧。因此，在这项研究中，合成、表征了四种新 ARA 烷基醚的区域异构混合物，并作为 EET 类似物评估了顺铂在猪近端肾小管上皮细胞中的浓度和时间依赖性毒性。所有四个醚基团都显示出生物电子等排体活性，范围从甲氧基- ( 1 ) 的边缘，到正丙氧基- ( 4 ) 的良好，以及乙氧基- ( 2 ) 和异丙氧基- ( 3 ) 的优异。化合物2和3对高、急性顺铂暴露表现出与 EET 区域异构体混合物 ( 5 ) 相当的细胞保护作用，但对低至中度、慢性暴露更有效。化合物2和3 （和5 ）通过稳定线粒体跨膜电位和减弱活性氧来发挥作用，导致丝裂原激活蛋白激酶 p38 和 JNK 的磷酸化减少，并减少 caspase-9 和 caspase-3 的活化。这项研究表明，烷氧基是 EET 内环氧化物的有效且代谢更稳定的生物等排体替代品，可实现不依赖于 sEH 的活性。它还说明了 EET 和其他环氧脂肪酸的醚基模拟物作为有前途的肾保护剂的潜力，可以在不损害其抗肿瘤功能的情况下解决顺铂的临床相关副作用。

更新日期：2021-12-20

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