Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2.
Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2.
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DOI：
10.1039/c6sc02758j
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发表时间：
2016-12-01
期刊：
影响因子：
8.4
通讯作者：
Brik A
中科院分区：
文献类型：
--
作者：
Gopinath P;Mahammed A;Ohayon S;Gross Z;Brik A
一种由有机合成、电化学、电催化和细胞研究组成的多学科方法，用于将 1,2-萘醌支架的分子特征与其 ROS 生成能力相关联。 最近的研究表明，通过诱导活性氧（ROS）形成的小分子选择性靶向癌细胞中过度表达的酶可能是癌症治疗的一种可行方法。其中一个例子是 β-拉帕酮 (β-lapachone) 使泛素特异性蛋白酶 2 (USP2) 失活，泛素特异性蛋白酶 2 (USP2) 是一种新兴的抗击前列腺癌的药物靶标，已发现β-拉帕酮涉及催化半胱氨酸的硫醇残基氧化为亚磺酸。合理设计具有改进活性的 β-拉帕酮类似物需要更好地了解决定此类分子产生 ROS 的变量。这一关键方面是通过调节其 1,2-萘醌支架并建立结构/活性关系来解决的，涉及其将分子氧还原为 ROS 的能力。还考察了同系列化合物对USP2酶活性的抑制作用。从这些研究中得出的一个结论是，β-拉帕酮中的邻醌基序比对醌基序和一些批准的醌类药物更适合催化氧还原。从一系列具有邻醌基序的化合物中获得的更广泛的结论是，只有氧化还原电位在 –0.3 ± 0.1 V 的狭窄范围内（相对于 pH 7.5 水缓冲液中的 Ag/AgCl）的试剂才能诱导 ROS 的形成。 ROS 产生能力和 USP2 抑制效力之间的良好相关性强调，相对简单、快速和可靠的小分子电催化氧还原测试可用于筛选和评估类似靶点的新候选药物。
A multidisciplinary approach, composed of organic synthesis, electrochemistry, electrocatalysis and cellular studies, for correlating the molecular features of a 1,2-naphthoquinone scaffold with its ROS generating ability. Recent studies have suggested that selective targeting of overexpressed enzymes in cancer cells by small molecules that induce the formation of reactive oxygen species (ROS) could be a viable approach in cancer therapy. One such example is the inactivation of ubiquitin specific protease-2 (USP2)—an emerging drug target to combat prostate cancer—by β-lapachone, which has been identified to involve oxidation of the catalytic cysteine's thiol residue to sulfinic acid. A rational design of β-lapachone analogs with improved activity requires a much better understanding of the variables that determine ROS production by this class of molecules. This crucial aspect was addressed via modulation of its 1,2-naphthoquinone scaffold and establishment of a structure/activity relationship, regarding its ability to reduce molecular oxygen to a ROS. The same series of compounds was also examined in terms of their inhibitory effect on the enzymatic activity of USP2. One deduction from these investigations was that the ortho-quinone motif in β-lapachone is much better suited for the catalytic reduction of oxygen than the para-quinone motif and some approved quinone based drugs. A broader conclusion, obtained from the series of compounds with ortho-quinone motifs, is that only the agents whose redox potential is in the narrow range of –0.3 ± 0.1 V (vs. Ag/AgCl in pH 7.5 aqueous buffer) induce the formation of ROS. The excellent correlation between the ROS production ability and the USP2 inhibition potency emphasizes that the relatively easy, fast, and reliable testing of electrocatalytic oxygen reduction by small molecules might be applied to screening and evaluating new drug candidates for similar targets.