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Design of Novel 2-Phenylquinazolin-4-amines as Selective CYP1B1 Inhibitors for Overcoming Paclitaxel Resistance in
Meixian Yang1, Fengyuan Yang2, Xinyue Huang3
1Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
Abstract:
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.
Insights
Researchers developed novel 2-phenylquinazolin-4-amine compounds to inhibit Cytochrome P450 1B1 (CYP1B1), a key factor in chemotherapy resistance. Compound 14b showed potent CYP1B1 inhibition, and several compounds reduced drug resistance and cancer cell migration.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Biology
Background:
- Overexpression of Cytochrome P450 1B1 (CYP1B1) in tumors leads to metabolic inactivation of chemotherapeutics, causing drug resistance.
- Selective inhibition of CYP1B1 is a promising strategy to overcome multidrug resistance in cancer therapy.
Purpose of the Study:
- To design, synthesize, and evaluate novel 2-phenylquinazolin-4-amine derivatives as potent and selective CYP1B1 inhibitors.
- To investigate the potential of these compounds in reversing drug resistance and inhibiting cancer cell migration and invasion.
Main Methods:
- Synthesis of a series of 2-phenylquinazolin-4-amine derivatives.
- In vitro enzymatic assays to determine CYP1B1 inhibitory activity and selectivity.
- Molecular docking studies to elucidate binding interactions.
- Cell-based assays to assess reversal of paclitaxel resistance and inhibition of cell migration/invasion in A549 cells.
- Radioiodine labeling for metabolic pathway analysis.
Main Results:
- Several synthesized compounds exhibited significant CYP1B1 inhibitory activity and improved water solubility.
- Compound 14b demonstrated exceptional efficacy and selectivity as a CYP1B1 inhibitor.
- Molecular docking indicated that π-system expansion, amine group, and iodine atom enhance binding affinity.
- Compounds 14a, 14b, and 14e effectively reduced paclitaxel resistance in A549 cells and inhibited their migration and invasion.
- Radioiodine labeling revealed the metabolic pathway of compound 5l, suggesting potential for 125I-5l as a radioactive probe.
Conclusions:
- Novel 2-phenylquinazolin-4-amine derivatives are potent CYP1B1 inhibitors with potential to overcome chemotherapy resistance.
- Compound 14b is a highly promising lead for further development.
- The identified compounds also possess anti-migratory and anti-invasive properties.
- Radioiodinated compound 5l may serve as a valuable tool for future research.
