期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 72, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128872
关键词
CYP450 mechanism; Heme chemistry; Thioester metabolism; O-18 tracing; Baeyer-Villiger oxidation
This study investigated the metabolism pathway of clopidogrel and found that the previous proposed reaction mechanism may be incorrect. Experimental results showed that M11 does not undergo the predicted hydrolytic reaction, but is formed via a Baeyer-Villiger-like mechanism to generate the active metabolite M13. This research provides a biochemical basis for clinical pharmacology and expands our understanding of CYP catalysis.
The serendipitous prodrug clopidogrel (CPG, M0) is the mainstay antiplatelet drug in clinical use. The thiophene moiety of CPG undergoes ring opening to form the active metabolite (M13) through two steps of cytochrome P450 (CYP)-catalyzed oxidation. The stable intermediate resulting from the first oxidation, 2-oxo-CPG (M2), is proposed to be oxidized to form an S-oxide intermediate (M11), which proceeds with a hydrolytic pathway to yield a sulfenic acid (M12) and subsequently the bioreduced active metabolite (M13). To test the long-standing pathway of M2 to M13 via M11, we have chemically synthesized M11 but found it does not undergo the proposed hydrolytic activation in various conditions including in liver microsomal incubations. To seek an alternative mechanism, O-18 tracing studies were performed with both (H2O)-O-18 and O-18(2), and LC-MS studies show that the carboxylate product moiety acquires its O-atom from oxygen instead of water, which rules out M11 as the bioactivation intermediate. To explain the O-18 tracing results, a one-step Baeyer-Villiger-like mechanism is proposed for the CYP-dependent thioester cleavage, which features the incorporation of the two O-atoms of O-2 into the two product moieties of carboxylate and sulfenic acid. The research presented herein provides a biochemical basis for delineating the clinical pharmacology of a mainstay treatment and expands our under-standing of CYP catalysis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据