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

Abstract

PurposeEstrogens 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.MethodsThe 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.ResultsOnly 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.ConclusionCu 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.

Derivatives (halogen, nitro and amino) of 8-hydroxyquinoline with highly potent antimicrobial and antioxidant activities

“…Cytotoxicity of compounds ( 1 – 9 ) was performed using a normal embryonic lung cell line (MRC-5) [12] . Briefly, the MRC-5 cells were grown in a DMEM medium that was supplemented with 100 U/mL of penicillin-streptomycin and 10% FBS.…”

“…In addition, NQ has been approved by the Food and Drug Administration (FDA), and is widely used as an antineurodegenerative drug to treat Alzheimer's disease and cancer in humans [6] . Moreover, metal complexes in 8HQ have been reported to enhance 8HQ bioactivities [12] . The search for novel potent lead compounds and repositioning of the well-known compounds/drugs for therapeutic applications are the main challenges [13] , [14] , [15] , [16] .…”

Organoruthenium(II) Complexes Bearing an Aromatase Inhibitor: Synthesis, Characterization, in Vitro Biological Activity and in Vivo Toxicity in Zebrafish Embryos

“…It was recently reported that the coordination of hydroquinoline, aminoquinoline and uracyl ligands to copper can lead to cytotoxic complexes with an aromatase inhibitory activity. 22,23 To our knowledge, only a few investigations from other groups involved the preparation of clinically-approved letrozole (Cu, Co, Ni) 24,25 or anastrozole (Pt) 26 metal complexes, and none of these studies reported an assessment of their aromatase inhibitory activity. Organoruthenium complexes are of particular interest for their activity against numerous types of cancer cells via multiple mechanisms, and are often considered as interesting alternatives to currently used therapeutics.…”

Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

“…The aromatase inhibitory activity of compounds 1 - 11 was investigated by the method previously described by Stresser et al (Stresser et al, 2000[ 43 ]), with minor modifications (Prachayasittikul et al, 2014[ 34 ]). The assay was performed with a Gentest kit using enzyme CYP19 and DBF as a fluorometric substrate.…”