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

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Design of Novel 2-Phenylquinazolin-4-amines as Selective CYP1B1 Inhibitors for Overcoming Paclitaxel Resistance in A549 Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-20 , DOI: 10.1021/acs.jmedchem.4c00164
Meixian Yang ₁ , Fengyuan Yang ₂ , Xinyue Huang ₃ , Jiajing Cai ₁ , Yuxin Zhang ₁ , Jianhua Jia ₁ , Dachuan Qiu ₁

Affiliation

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 π-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.

中文翻译：

新型 2-苯基喹唑啉-4-胺作为选择性 CYP1B1 抑制剂的设计，用于克服 A549 细胞中的紫杉醇耐药性

当细胞色素 P450 1B1 (CYP1B1) 在肿瘤细胞中过度表达时，会导致化疗药物的代谢失活。 CYP1B1 的选择性抑制有望逆转耐药性。为了追求有效的 CYP1B1 抑制剂，我们设计并合成了一系列 2-苯基喹唑啉-4-胺。这些新开发的抑制剂中很大一部分表现出对 CYP1B1 的抑制活性，同时改善了水溶性。值得注意的是，化合物14b对 CYP1B1 表现出优异的抑制功效和选择性。分子对接研究表明，通过芳构化、引入胺基和碘原子来扩展π-系统增强了结合亲和力。此外，抑制剂14a 、 14b和14e表现出显着降低A549细胞对紫杉醇的耐药性的能力，同时还抑制这些细胞的迁移和侵袭。最后，放射性碘标记实验揭示了化合物5l在小鼠体内的代谢途径，突出了¹²⁵ I- 5l作为未来研究工作放射性探针的潜力。

更新日期：2024-03-20

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