Synthesis of ortho-Formylphenylphosphonic Acids as Covalent Probes of Active Site Lysines.
Synthesis of ortho-Formylphenylphosphonic Acids as Covalent Probes of Active Site Lysines.
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作为活性位点赖氨酸共价探针的邻甲酰基苯基膦酸的合成。
DOI：
10.1080/10426507.2018.1539996
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
McKenna,CharlesE
中科院分区：
文献类型：
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作者：
Duro,MarlonVincentV;Alnajjar,KhadijehS;Sweasy,JoannB;Kashemirov,BorisA;McKenna,CharlesE
在使用小分子靶向抑制DNA聚合酶β（pol β）裂解酶活性的研究过程中，我们观察到在碱性水溶液条件下（2-甲酰基）苯基膦酸（2FPP）和丁胺之间形成醛亚胺;需要膦酸酯基团完全去质子化以稳定亚胺产物。计算对接研究的结果表明，近端膦酸盐可以促进裂合酶活性位点上的Lys-72与醛基的反应，这不仅是因为膦酸盐能够模拟磷酸盐与DNA结合位点相互作用，而且还因为它能够保护亚胺免受水解。因此，使用具有胺连接体的2FPP类似物制备新型聚β裂解酶抑制剂;使用钯催化的微波辅助Michaelis-Arbuzov化学，在合成该中间体时，可以与未保护的醛形成P-C键。在pol β测定中评价了这些化合物和缺乏醛或膦酸酯的结构相关衍生物，以评估其抑制潜力。
During the course of an investigation of targeted inhibition of DNA polymerase beta (pol β) lyase activity using small molecules, we observed the formation of an aldimine between (2-formyl)phenylphosphonic acid (2FPP) and butylamine under basic aqueous conditions; complete deprotonation of the phosphonate group was required to stabilize the imine product. Results of computational docking studies suggested that the reaction of Lys-72 on the lyase active site with an aldehyde group could be facilitated by a proximal phosphonate, not only because of the phosphonate’s ability to mimic phosphate interacting with the DNA binding site, but also because of its ability to shield the imine against hydrolysis. Novel pol β lyase inhibitors were thus prepared using a 2FPP analogue with an amine linker; P-C bond formation in synthesis of this intermediate was possible with an unprotected aldehyde using palladium-catalyzed, microwave-assisted Michaelis–Arbuzov chemistry. These compounds, and structurally related derivatives lacking the aldehyde or phosphonate, were evaluated in an assay for pol β to assess their potential for inhibition.