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

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.

细胞色素P450 1B1（CYP1B1）在肿瘤细胞中过表达时，可参与化疗药物的代谢灭活过程。选择性抑制CYP1B1有望逆转肿瘤多药耐药性。本研究在开发强效CYP1B1抑制剂的过程中，设计并合成了一系列2-苯基喹唑啉-4-胺类化合物。其中相当比例的新型抑制剂展现出针对CYP1B1的抑制活性，同时水溶性得到显著改善。值得注意的是，化合物14b对CYP1B1表现出优异的抑制活性与选择性。分子对接研究表明，通过芳构化扩展π系统、引入氨基与碘原子可增强化合物与靶点的结合亲和力。此外，抑制剂14a、14b与14e可显著降低A549细胞对紫杉醇的耐药性，同时抑制该细胞的迁移与侵袭能力。最后，放射性碘标记实验阐明了化合物5l在小鼠体内的代谢通路，凸显了125I-5l作为放射性探针用于后续研究的潜在价值。