Design, Synthesis, and Evaluation of 18F-Labeling CYP1B1 PET Tracer Based on 2-Phenylquinazolin

Cai, Jiajing; Yi, Lan; Xia, Zhu; Huang, Xinyue; Yang, Meixian; Zhao, Zhenghuan; Gao, Chenyang; Yang, Hengyi; Zhang, Jiayuan; Peng, Zhiping; Qiu, Dachuan

doi:10.1016/j.bmcl.2023.129533

Cited by 1 publication

(1 citation statement)

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“…Moreover, we anticipated that the nitrogen atom could engage in hydrogen bonding with CYP1B1 and become acidified to form hydrochlorides, ultimately enhancing water solubility. To validate these hypotheses, we synthesized the compound 6k and conducted an EROD assay to evaluate its inhibitory activity against CYP1B1 based on our previous work. , Notably, as a structural derivative of 1b , compound 6k exhibited significantly stronger inhibition to CYP1B1 compared with 1b , with IC 50 values of 0.49 and 2.0 nM, respectively. Additionally, the CLog P values calculated with ChemDraw, indicated that compound 6k possessed significantly improved water solubility compared with 1b , with values of 2.71 and 3.82, respectively.…”

Section: Introductionmentioning

confidence: 99%

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

Yang,

Huang

et al. 2024

J. Med. Chem.

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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.

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Section: Introductionmentioning

confidence: 99%