The human 2‐oxoglutarate (2OG)‐dependent oxygenase aspartate/asparagine‐β‐hydroxylase (AspH) is a potential medicinal chemistry target for anticancer therapy. AspH is present on the cell surface of invasive cancer cells and accepts epidermal growth factor‐like domain (EGFD) substrates with a noncanonical (i. e., Cys 1–2, 3–4, 5–6) disulfide pattern. We report a concise synthesis of C‐3‐substituted derivatives of pyridine‐2,4‐dicarboxylic acid (2,4‐PDCA) as 2OG competitors for use in SAR studies on AspH inhibition. AspH inhibition was assayed by using a mass spectrometry‐based assay with a stable thioether analogue of a natural EGFD AspH substrate. Certain C‐3‐substituted 2,4‐PDCA derivatives were potent AspH inhibitors, manifesting selectivity over some, but not all, other tested human 2OG oxygenases. The results raise questions about the use of pyridine‐carboxylate‐related 2OG analogues as selective functional probes for specific 2OG oxygenases, and should aid in the development of AspH inhibitors suitable for in vivo use.

中文翻译：

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作为人天冬氨酸/天冬酰胺-β-羟化酶小分子抑制剂的新型吡啶-羧酸盐的合成。

人类 2-氧代戊二酸 (2OG) 依赖性加氧酶天冬氨酸/天冬酰胺-β-羟化酶 (AspH) 是抗癌治疗的潜在药物化学靶点。AspH 存在于侵袭性癌细胞的细胞表面，并接受具有非典型（即 Cys 1-2、3-4、5-6）二硫键模式的表皮生长因子样结构域 (EGFD) 底物。我们报告了吡啶-2,4-二羧酸 (2,4-PDCA) 的 C-3 取代衍生物作为 2OG 竞争剂的简明合成，用于 AspH 抑制的 SAR 研究。AspH 抑制是通过使用基于质谱的测定法和天然 EGFD AspH 底物的稳定硫醚类似物来测定的。某些 C-3 取代的 2,4-PDCA 衍生物是有效的 AspH 抑制剂，表现出对一些（但不是全部）其他测试过的人类 2OG 加氧酶的选择性。体内使用。