Design of Novel 2-Phenylquinazolin-4-amines as Selective CYP1B1 Inhibitors for Overcoming Paclitaxel Resistance in A549 Cells

作者全名："Yang, Meixian; Yang, Fengyuan; Huang, Xinyue; Cai, Jiajing; Zhang, Yuxin; Jia, Jianhua; Qiu, Dachuan"

作者地址："[Yang, Meixian; Cai, Jiajing; Zhang, Yuxin; Jia, Jianhua; Qiu, Dachuan] Chongqing Med Univ, Coll Basic Med Sci, Dept Radiat Med, Chongqing 400016, Peoples R China; [Yang, Fengyuan] Chongqing Univ, Sch Pharmaceut Sci, Chongqing 400044, Peoples R China; [Yang, Fengyuan] Chongqing Univ, Innovat Drug Res Ctr, Chongqing 400016, Peoples R China; [Huang, Xinyue] Chongqing Univ Technol, Coll Chem & Chem Engn, Chongqing 400054, Peoples R China"

通信作者："Qiu, DC (通讯作者)，Chongqing Med Univ, Coll Basic Med Sci, Dept Radiat Med, Chongqing 400016, Peoples R China."

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:001189799400001

JCR分区：Q1

影响因子：6.8

年份：2024

卷号：67

期号：7

开始页：5883

结束页：5901

文献类型：Article

关键词：　

摘要："Cytochrome P450 1B1 (CYP1B1) contributes to the metabolic inactivation of chemotherapeutics when overexpressed in tumor cells. Selective inhibition of CYP1B1 holds promise for reversing drug resistance. In our pursuit of potent CYP1B1 inhibitors, we designed and synthesized a series of 2-phenylquinazolin-4-amines. A substantial proportion of these newly developed inhibitors demonstrated inhibitory activity against CYP1B1, accompanied by improved water solubility. Remarkably, compound 14b exhibited exceptional inhibitory efficacy and selectivity toward CYP1B1. Molecular docking studies suggested that the expansion of the pi-system through aromatization, the introduction of an amine group, and iodine atom augmented the binding affinity. Furthermore, inhibitors 14a, 14b, and 14e demonstrated the ability to significantly reduce the resistance in A549 cells to paclitaxel, while also inhibiting the migration and invasion of these cells. Finally, radioiodine labeling experiments shed light on the metabolic pathway of compound 5l in mice, highlighting the potential of 125I-5l as a radioactive probe for future research endeavors."

基金机构："National Natural Science Foundation of China [22371026, 82001869]; NSFC [CXQT21017]; Creative Research Group of CQ University [KJQN202200446]; Science and Technology Research Program of Chongqing Municipal Education Commission"

基金资助正文："The authors gratefully acknowledge research support of this work by NSFC (22371026, 82001869), Creative Research Group of CQ University (CXQT21017), and the Science and Technology Research Program of Chongqing Municipal Education Commission (grant no. KJQN202200446)."