The transcription factor NRF2 controls resistance to oxidative insult and is thus a key therapeutic target for treating a number of disease states associated with oxidative stress and aging. We previously reported CBR-470-1, a bis-sulfone which activates NRF2 by increasing the levels of methylglyoxal, a metabolite that covalently modifies NRF2 repressor KEAP1. Here, we report the design, synthesis, and structure activity relationship of a series of bis-sulfones derived from this unexplored chemical template. We identify analogs with sub-micromolar potencies, 7f and 7g, as well as establish that efficacious NRF2 activation can be achieved by non-toxic analogs 7c, 7e, and 9, a key limitation with CBR-470-1. Further efforts to identify non-covalent NRF2 activators of this kind will likely provide new insight into revealing the role of central metabolism in cellular signaling.

转录因子 NRF2 控制对氧化损伤的抵抗力，因此是治疗许多与氧化应激和衰老相关的疾病状态的关键治疗靶点。我们之前报道了 CBR-470-1，一种双砜，它通过增加甲基乙二醛的水平来激活 NRF2，甲基乙二醛是一种共价修饰 NRF2 阻遏物 KEAP1 的代谢物。在这里，我们报告了从这个未开发的化学模板衍生的一系列双砜的设计、合成和结构活性关系。我们鉴定了具有亚微摩尔效力的类似物7f和7g，并确定无毒类似物可以实现有效的 NRF2 激活7c、7e和9，CBR-470-1 的一个关键限制。进一步努力确定这种非共价 NRF2 激活剂可能会为揭示中枢代谢在细胞信号传导中的作用提供新的见解。