<br>托卡朋、恩他卡朋和新型硝基儿茶酚衍生物的细胞和线粒体毒性,ACS Pharmacology & Translational Science

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托卡朋、恩他卡朋和新型硝基儿茶酚衍生物的细胞和线粒体毒性
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2024-04-30 , DOI: 10.1021/acsptsci.4c00124
Miguel Pinto _{1,

2,

3} , Tiago Barros Silva _{1,

2,

3} , Vilma A Sardão _{4,

5} , Rui Simões _{4,

6} , Bárbara Albuquerque _{1,

7} , Paulo J Oliveira _{4,

6} , Maria João Valente _{2,

3} , Fernando Remião _{2,

3} , Patrício Soares-da-Silva ₇ , Carlos Fernandes ₁ , Fernanda Borges ₁

Affiliation

硝基儿茶酚是开发儿茶酚O -甲基转移酶 (COMT) 强效紧密结合抑制剂的标准药效团，可用作治疗帕金森病的辅助药物。托卡朋是此类药物中最有效的药物，但由于其可能引起肝损伤，因此引起了安全问题。托卡朋引起的肝毒性归因于硝基儿茶酚部分；然而，其他基于硝基儿茶酚的 COMT 抑制剂（例如恩他卡朋）是安全的，不会损害肝脏。关于哪些机制和化学性质决定基于硝基儿茶酚的 COMT 抑制剂的毒性，目前存在知识差距。通过大量基于细胞的检测，我们发现托卡朋诱导的毒性是由直接干扰线粒体引起的，而不依赖于 P450 的生物激活。我们的研究结果还表明，(a) 亲脂性是硝基儿茶酚潜在毒性的一个关键特性； (b)直接连接到硝基儿茶酚环上的羰基的存在似乎增加了分子的反应性，并且(c)双键中氰基部分的存在稳定了反应性，降低了细胞毒性。总而言之，硝基儿茶酚环的 C1 取代基的亲脂性和化学性质之间的良好平衡可以解释托卡朋和恩他卡朋之间观察到的毒理学行为的差异。

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Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives

Nitrocatechols are the standard pharmacophore to develop potent tight-binding inhibitors of catechol O-methyltransferase (COMT), which can be used as coadjuvant drugs to manage Parkinson’s disease. Tolcapone is the most potent drug of this class, but it has raised safety concerns due to its potential to induce liver damage. Tolcapone-induced hepatotoxicity has been attributed to the nitrocatechol moiety; however, other nitrocatechol-based COMT inhibitors, such as entacapone, are safe and do not damage the liver. There is a knowledge gap concerning which mechanisms and chemical properties govern the toxicity of nitrocatechol-based COMT inhibitors. Using a vast array of cell-based assays, we found that tolcapone-induced toxicity is caused by direct interference with mitochondria that does not depend on bioactivation by P450. Our findings also suggest that (a) lipophilicity is a key property in the toxic potential of nitrocatechols; (b) the presence of a carbonyl group directly attached to the nitrocatechol ring seems to increase the reactivity of the molecule, and (c) the presence of cyano moiety in double bond stabilizes the reactivity decreasing the cytotoxicity. Altogether, the fine balance between lipophilicity and the chemical nature of the C1 substituents of the nitrocatechol ring may explain the difference in the toxicological behavior observed between tolcapone and entacapone.

更新日期：2024-04-30

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