硫芥衍生物2-氯乙基乙硫醚的有效中和剂甲巯咪唑

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-08-09 DOI:10.1021/acsbiomedchemau.2c00087
Albert Armoo, Tanner Diemer, Abigail Donkor, Jerrod Fedorchik, Severine Van slambrouck, Rachel Willand-Charnley and Brian A. Logue*, 
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引用次数: 0

摘要

硫芥(SM)被军方指定为HD,是一种剧毒和危险的发泡剂,自第一次世界大战以来一直被用作化学战剂。尽管SM有着悠久的历史,但目前还不存在有效的解药。SM的作用主要基于其烷基化重要生物分子的能力。此外,由于SM的一部分可能在初次接触后几天内保持未反应,因此存在在暴露后几天直接中和未反应SM的机会窗口。在这项研究中,我们评估了多个亲核分子的结构-活性关系,以中和SM的单功能类似物2-氯乙基乙基硫醚(CEES)对人类角质形成细胞(HaCaT)的毒性作用。分别通过MTT、细胞-基质粘附(CMA)和凋亡蛋白标记物测定测定细胞活力、细胞外基质粘附的相对损失和CEES引起的细胞凋亡。一组五种具有不同官能团的二碳化合物作为第一代中和剂的初步组,以调查减轻CEES的毒性作用与官能团亲核性之间的相关性。除了产生附加毒性的氨基酸外,我们通常观察到随着亲核性的增加,对细胞毒性的保护作用也在增加。我们将这种治疗策略扩展到第二代试剂,其中包含从第一代分子中鉴定出的有利结构特征。我们的研究结果表明,目前美国食品药品监督管理局批准的用于治疗甲状腺功能亢进症的药物甲巯咪唑(MIZ)有效降低了细胞毒性,增加了CMA,并减少了由CEES毒性引起的细胞凋亡。MIZ与CEES选择性反应,在培养基和细胞裂解物处理中产生2-(2-(乙基硫代)乙基硫代)-1-甲基-1H-咪唑(EEMI),从而降低毒性。基于这些结果,MIZ作为SM治疗药物的未来发展可能提供一种可行的方法来降低SM的即时和长期毒性,也可能有助于减轻由于残留完整SM而导致的SM毒性的缓慢发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Methimazole, an Effective Neutralizing Agent of the Sulfur Mustard Derivative 2-Chloroethyl Ethyl Sulfide

Sulfur mustard (SM), designated by the military as HD, is a highly toxic and dangerous vesicant that has been utilized as a chemical warfare agent since World War I. Despite SM’s extensive history, an effective antidote does not exist. The effects of SM are predominantly based on its ability to alkylate important biomolecules. Also, with the potential for a fraction of SM to remain unreacted up to days after initial contact, a window of opportunity exists for direct neutralization of unreacted SM over the days following exposure. In this study, we evaluated the structure–activity relationship of multiple nucleophilic molecules to neutralize the toxic effects of 2-chloroethyl ethyl sulfide (CEES), a monofunctional analogue of SM, on human keratinocyte (HaCaT) cells. Cell viability, relative loss of extracellular matrix adhesions, and apoptosis caused by CEES were measured via MTT, cell–matrix adhesion (CMA), and apoptosis protein marker assays, respectively. A set of five two-carbon compounds with various functional groups served as a preliminary group of first-generation neutralizing agents to survey the correlation between mitigation of CEES’s toxic effects and functional group nucleophilicity. Apart from thioacids, which produced additive toxicity, we generally observed the trend of increasing protection from cytotoxicity with increasing nucleophilicity. We extended this treatment strategy to second-generation agents which contained advantageous structural features identified from the first-generation molecules. Our results show that methimazole (MIZ), a currently FDA-approved drug used to treat hyperthyroidism, effectively reduced cytotoxicity, increased CMA, and decreased apoptosis resulting from CEES toxicity. MIZ selectively reacts with CEES to produce 2-(2-(ethylthio)ethylthio)-1-methyl-1H-imidazole (EEMI) in media and cell lysate treatments resulting in the reduction of toxicity. Based on these results, future development of MIZ as an SM therapeutic may provide a viable approach to reduce both the immediate and long-term toxicity of SM and may also help mitigate slower developing SM toxicity due to residual intact SM.

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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
发文量
0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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