Synthesis, antioxidant and structural properties of modified ebselen derivatives and conjugates.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Adrian I Doig, Kai N Sands, Bienca Boongaling, Wen Zhou, Thomas G Back
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引用次数: 0

Abstract

Ebselen is a drug in clinical trials for several diseases and degenerative conditions where oxidative stress is implicated. A series of novel ebselen analogues was synthesized, including hydroxy-, alkoxy- and aminomethylene derivatives, as well as hybrid species where the ebselen selenium atom is shared with other potent antioxidant structures, such as cyclic selenenyl sulfide, cyclic seleninate ester and spirodioxyselenurane moieties. Conjugates of ebselen with cholesterol, prednisolone and the radical inhibitor BHT were also prepared. The products were tested for antioxidant activity in an NMR-based assay by measuring the rate of consumption of benzyl thiol or the production of dibenzyl disulfide in the presence of hydrogen peroxide when catalyzed by the ebselen analogues. Activities ranged from 12 to 0.12 times that of ebselen. The oxidation of the 2-hydroxymethylene derivative of ebselen was faster than thiolysis in the initial step and the overall rate was further accelerated under basic conditions. The corresponding selenenyl sulfide analogue underwent very slow disproportionation under neutral conditions that was enhanced by the presence of a base catalyst. During investigation of possible fluxional behaviour of a bis-amide analogue, an unusual tetraphenyphosphonium salt of a tricoordinate selenium pincer anion was discovered with exceptionally potent catalytic activity, 130 times that of ebselen. In addition to rate measurements, X-ray crystallography and DFT computational methods were also employed to gain further structural and mechanistic insights.

改性依布硒衍生物和共轭物的合成、抗氧化性和结构特性。
依布硒是一种正在进行临床试验的药物,可用于治疗多种涉及氧化应激的疾病和退行性病症。我们合成了一系列新型依布硒类似物,包括羟基、烷氧基和氨甲基衍生物,以及依布硒硒原子与其他强效抗氧化剂结构(如环硒硫醚、环硒酸酯和螺二氧硒脲分子)共用的杂交品种。此外,还制备了依布硒与胆固醇、泼尼松龙和自由基抑制剂 BHT 的共轭物。在一种基于核磁共振的检测方法中,通过测量依布硒类似物在过氧化氢催化下苄基硫醇的消耗率或二苄基二硫化物的生成率,对这些产品的抗氧化活性进行了测试。活性是依布硒的 12 至 0.12 倍不等。在初始阶段,依布硒的 2-羟基亚甲基衍生物的氧化速度比硫化速度快,而在碱性条件下,总体速度进一步加快。相应的硒基硫醚类似物在中性条件下发生的歧化反应非常缓慢,而碱催化剂的存在则提高了这种反应的速度。在研究双酰胺类似物的可能通性时,发现了一种不寻常的三配位硒钳阴离子的四苯基鏻盐,其催化活性特别强,是依布硒的 130 倍。除速率测量外,还采用了 X 射线晶体学和 DFT 计算方法,以进一步了解其结构和机理。
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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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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