PDF(Pubmed)
Abstract：
Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon-carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H2 18O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) site of N-protected pyridin-2-amines, and the other occurs by a pseudo-retro-aldol reaction after hydroxylation of a C(sp3) site. This is the first report of CYP3A-mediated C-C bond cleavage in drug metabolism via ipso-addition of oxygen mediated mechanism. CYP3A-mediated ipso-addition is also implicated in the regioselective C-C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A-catalyzed oxygen ipso-addition under environmentally friendly conditions may be attractive and inspire biomimetic or P450-engineering methods to address the challenging task of C-C bond cleavages.
摘要：
哺乳动物细胞色素P450药物代谢酶很少切割碳-碳（C-C）键，并且这种切割的机制在很大程度上是未知的。我们发现了两个不寻常的非极性裂缝，FDA批准的酪氨酸激酶抑制剂pexidartinib中的无应变C（sp2）-C（sp3）键由CYP3A4/5介导，CYP3A4/5是主要的人类I期药物代谢酶。使用合成酮，我们排除了Baeyer-Villiger氧化机制，该机制通常用于解决P450介导的C-C键断裂。我们在富含18O2和H218O的系统中的研究揭示了C-C键裂解的两种不寻常的不同机制：一个键被CYP3A介导的氧向N-保护的吡啶-2-胺的C（sp2）位点的ipso加成，另一种是在C（sp3）位点羟基化后通过假逆醛醇反应发生。这是CYP3A介导的C-C键裂解在药物代谢中通过氧介导的ipso加成机制的首次报道。CYP3A介导的ipso加成也涉及几种帕西达尼类似物的区域选择性C-C切割。在环境友好的条件下，CYP3A催化的氧ipso加成的区域特异性可能具有吸引力，并激发了仿生或P450工程方法来解决C-C键裂解的挑战性任务。
