Synthesis and biological evaluation of coumarin derivatives as selective CYP2A6 inhibitors
Synthesis and biological evaluation of coumarin derivatives as selective CYP2A6 inhibitors
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DOI：
10.1016/j.bmcl.2023.129206
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发表时间：
2023-03-24
影响因子：
2.7
通讯作者：
Oda，Kazuaki
中科院分区：
文献类型：
--
作者：
Yamaguchi，Yuki;Nishizono，Naozumi;Oda，Kazuaki
细胞色素P450 2A6 （CYP2A6）抑制剂有望用于戒烟辅助和癌症预防。由于典型的以香豆素为基础的CYP2A6抑制剂甲氧沙伦也抑制CYP3A4，意外的药物-药物相互作用仍然是一个问题。因此，开发选择性CYP2A6抑制剂是必要的。在本研究中，我们合成了基于香豆素的分子，确定了抑制CYP2A6的ic50值，验证了基于机制的抑制的可能性，并比较了CYP2A6和CYP3A4的选择性。结果表明，我们开发的CYP2A6抑制剂比甲氧沙林更有效，更有选择性。
Cytochrome P450 2A6 (CYP2A6) inhibitors are expected to be suitable as smoking cessation aids and for cancer prevention. Because the typical coumarin-based CYP2A6 inhibitor methoxsalen also inhibits CYP3A4, unintended drug-drug interactions are still a concern. Therefore, the development of selective CYP2A6 inhibitors is desirable. In this study, we synthesized coumarin-based molecules, determined the IC50values for CYP2A6 inhibition, verified the possibility of mechanism-based inhibition, and compared the selectivity for CYP2A6 versus CYP3A4. The results demonstrated that we developed CYP2A6 inhibitors that were more potent and selective than methoxsalen.