Tryptophan oxidation in biology has been recently implicated in a vast array of paramount pathogenic conditions in humans, including multiple sclerosis, rheumatoid arthritis, type-I diabetes, and cancer. This 2,3-dioxygenative cleavage of the indole ring of tryptophan with dioxygen is mediated by two heme enzymes, tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), during its conversion to N-formylkynurenine in the first and rate-limiting step of kynurenine pathway. Despite the pivotal significance of this enzymatic transformation, a vivid viewpoint of the precise mechanistic events is far from complete. A heme superoxide adduct is thought to be the active oxidant in both TDO and IDO, which, following O-O bond cleavage, presumably generates a key ferryl (FeIV=O) reaction intermediate. This study, for the first time in model chemistry, demonstrates the potential of synthetic heme superoxide adducts to mimic the bioinorganic chemistry of indole dioxygenation by TDO and IDO, challenging the widely accepted categorization of these metal adducts as weak oxidants. Herein, an electronically divergent series of ferric heme superoxo oxidants mediates the facile conversion of an array of indole substrates into their corresponding 2,3-dioxygenated products, while shedding light on an unequivocally occurring, putative ferryl intermediate. The oxygenated indole products have been isolated in ~31% yield, and characterized by LC-MS, 1H and 13C NMR, and FT-IR methodologies, as well as by 18O2(g) labeling experiments. Distinctly, the most electron-deficient superoxo adduct is observed to react the fastest, specifically with the most electron-rich indole substrate, underscoring the cruciality of electrophilicity of the heme superoxide moiety in facilitating the initial indole activation step. Comprehensive understanding of such mechanistic subtleties will benefit future attempts in the rational design of salient therapeutic agents, including next generation anticancer drug targets with amplified effectivity.

中文翻译：

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用血红素超氧化物模拟物模拟色氨酸/吲哚胺 2,3-双加氧酶：Ferryl 是关键中间体吗？

生物学中的色氨酸氧化最近与人类的多种重要致病条件有关，包括多发性硬化症、类风湿性关节炎、I 型糖尿病和癌症。色氨酸的吲哚环与双氧的 2,3-双氧裂解由两种血红素酶介导，色氨酸 2,3-双加氧酶 (TDO) 和吲哚胺 2,3-双加氧酶 (IDO)，在其转化为 N-甲酰基犬尿氨酸的过程中犬尿氨酸途径的第一步和限速步骤。尽管这种酶促转化具有关键意义，但对精确机械事件的生动观点还远未完成。血红素超氧化物加合物被认为是 TDO 和 IDO 中的活性氧化剂，在 OO 键断裂后，可能会产生关键的 Ferrel (FeIV=O) 反应中间体。这项研究，首次在模型化学中展示了合成血红素超氧化物加合物模拟 TDO 和 IDO 吲哚双氧化的生物无机化学的潜力，挑战了广泛接受的将这些金属加合物归类为弱氧化剂的分类。在本文中，一系列电子发散的三价铁血红素超氧氧化剂介导了一系列吲哚底物向其相应的 2,3-二氧化产物的轻松转化，同时揭示了明确存在的、假定的弗瑞尔中间体。氧化吲哚产物的分离产率约为 31%，并通过 LC-MS、1H 和 13C NMR、FT-IR 方法以及 18O2(g) 标记实验进行了表征。显然，最缺电子的超氧加合物被观察到反应最快，特别是对于最富电子的吲哚底物，强调了血红素超氧化物部分的亲电性在促进初始吲哚活化步骤中的关键性。对这种机制微妙之处的全面理解将有利于未来合理设计显着治疗剂的尝试，包括具有增强效果的下一代抗癌药物靶点。