Fluorinated derivatives of pyridine-2,4-dicarboxylate are potent inhibitors of human 2-oxoglutarate dependent oxygenases.
Fluorinated derivatives of pyridine-2,4-dicarboxylate are potent inhibitors of human 2-oxoglutarate dependent oxygenases.
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DOI：
10.1016/j.jfluchem.2021.109804
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发表时间：
2021-07
影响因子：
1.9
通讯作者：
Schofield CJ
中科院分区：
文献类型：
--
作者：
Brewitz L;Nakashima Y;Tumber A;Salah E;Schofield CJ
2，4-氟化吡啶-2，4-二羧酸(2，4-PDCA)衍生物的合成氟化2，4-PDCA衍生物抑制2-氧戊二酸依赖的加氧酶2，4-PDCA C5取代基提高ASPH对KDM4抑制的选择性2-氧代戊二酸(2OG)加氧酶在人体生物学中具有重要作用，是被证实的药物化学靶标。改善广谱20G加氧酶抑制剂的选择性图谱可能有助于识别用于功能分配工作的选择性抑制剂。报道了广谱2OG加氧酶抑制剂吡啶-2，4-二羧酸酯(2，4-PDCA)的F-和CF3-取代衍生物的合成。用基于质谱学的方法测定了它们对某些功能不同的人2OG加氧酶的抑制选择性。F-取代的2，4-PDCA衍生物对2OG加氧酶天冬氨酸/天冬酰胺-β羟基酶(ASPh)和JmjC赖氨酸专一性N-ε-脱甲基酶4E(KDM4E)的抑制作用均低于2，4-PDCA本身，但C5F-取代的2，4-PDCA衍生物对ASPH的抑制作用与2，4-PDCA相似。值得注意的是，在2，4-PDCA的C5位引入F-或CF3-取代基，与2，4-PDCA相比，ASPH的选择性比KDM4E有显著提高。结晶学研究在我们观察到的结构基础上提供了信息，这举例说明了对20G类似物进行微小的改变如何可以使20G加氧酶抑制的效力产生实质性的不同。
Synthesis of fluorinated pyridine-2,4-dicarboxylic acid (2,4-PDCA) derivatives Fluorinated 2,4-PDCA derivatives inhibit 2-oxoglutarate dependent oxygenases 2,4-PDCA C5 substituents increase the selectivity for AspH over KDM4 inhibition 2-Oxoglutarate (2OG) oxygenases have important roles in human biology and are validated medicinal chemistry targets. Improving the selectivity profile of broad-spectrum 2OG oxygenase inhibitors may help enable the identification of selective inhibitors for use in functional assignment work. We report the synthesis of F- and CF3-substituted derivatives of the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylate (2,4-PDCA). Their inhibition selectivity profile against selected functionally distinct human 2OG oxygenases was determined using mass spectrometry-based assays. F-substituted 2,4-PDCA derivatives efficiently inhibit the 2OG oxygenases aspartate/asparagine-β-hydroxylase (AspH) and the JmjC lysine-specific Nε-demethylase 4E (KDM4E); The F- and CF3-substituted 2,4-PDCA derivatives were all less efficient inhibitors of the tested 2OG oxygenases than 2,4-PDCA itself, except for the C5 F-substituted 2,4-PDCA derivative which inhibited AspH with a similar efficiency as 2,4-PDCA. Notably, the introduction of a F- or CF3-substituent at the C5 position of 2,4-PDCA results in a substantial increase in selectivity for AspH over KDM4E compared to 2,4-PDCA. Crystallographic studies inform on the structural basis of our observations, which exemplifies how a small change on a 2OG analogue can make a substantial difference in the potency of 2OG oxygenase inhibition.
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2-氧气谷物衍生物的合成及其作为人天冬氨酸/天冬酰胺-β-羟化酶的蛋白质和抑制剂的评估。
影响因子：
8.4
作者：
Brewitz L;Nakashima Y;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
3.8
作者：
Al-Qahtani, Khalid;Jabeen, Bushra;McCullagh, James S. O.
通讯作者：
McCullagh, James S. O.
影响因子：
15
作者：
BOTT, G;FIELD, LD;STERNHELL, S
通讯作者：
STERNHELL, S
影响因子：
7.3
作者：
Gillis, Eric P.;Eastman, Kyle J.;Meanwell, Nicholas A.
通讯作者：
Meanwell, Nicholas A.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH