Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

Abstract

Purpose

Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni) complexes of 8-hydroxyquinoline (8HQ) and uracil derivatives (4–9) were investigated for their aromatase inhibitory and cytotoxic activities.

Methods

The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.

Results

Only Cu complexes (6 and 9) exhibited aromatase inhibitory effect with IC₅₀ 0.30 and 1.7 μM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6), as well as free ligand 8HQ, exhibited activity with IC₅₀ range 0.74–6.27 μM.

Conclusion

Cu complexes (6 and 9) were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer and other estrogen-related diseases.

Keywords:

• aromatase inhibitor
• anticancer
• metal-based compound

Acknowledgments

This project was supported by the research grant of Srinakharinwirot University (BE 2555) and by the Office of the Higher Education Commission, Mahidol University under the National Research Universities Initiative. We gratefully acknowledge the Chulabhorn Research Institute for performing aromatase inhibition and cytotoxic assays.

Disclosure

The authors report no conflicts of interest in this work.