title: Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Veda
authors.initials: V
authors.lastname: Prachayasittikul
authors.affiliation: Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand.
authors.forename: Ratchanok
authors.initials: R
authors.lastname: Pingaew
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Chanin
authors.initials: C
authors.lastname: Nantasenamat
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Supaluk
authors.initials: S
authors.lastname: Prachayasittikul
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok, Thailand ; Chulabhorn Graduate Institute, Bangkok, Thailand.
authors.forename: Somsak
authors.initials: S
authors.lastname: Ruchirawat
authors.affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Virapong
authors.initials: V
authors.lastname: Prachayasittikul
mesh_terms: D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D056831:Coordination Complexes; D003300:Copper / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology; D000077289:Letrozole; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008345:Manganese / Q000737:chemistry; D009532:Nickel / Q000737:chemistry; D009570:Nitriles / Q000494:pharmacology; D015125:Oxyquinoline / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology; D014498:Uracil / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D056831:Coordination Complexes; D009570:Nitriles; D014230:Triazoles; D008345:Manganese; D014498:Uracil; D015125:Oxyquinoline; D003300:Copper; D000077289:Letrozole; D009532:Nickel; D007654:Ketoconazole
keywords: anticancer; aromatase inhibitor; metal-based compound