Discovery of 5-(or 6)-benzoxazoles and oxazolo[4,5-b]pyridines as novel candidate antitumor agents targeting hTopo II alpha

Karatas E., FOTO E., ERTAN BOLELLİ T., Yalcin-Ozkat G., YILMAZ S., Ataei S., ...Daha Fazla

BIOORGANIC CHEMISTRY, cilt.112, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 112
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.bioorg.2021.104913
  • Dergi Adı: BIOORGANIC CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Benzoxazoles, Oxazolo[4,5-b]pyridines, Topoisomerase I and II alpha inhibition, Antitumor, Molecular docking, Molecular dynamic simulation, DNA TOPOISOMERASE-II, DRUG DISCOVERY, INHIBITORS, PREDICTION, MECHANISM, DOCKING, CLEAVAGE, CELLS, MODEL, CAMPTOTHECIN
  • Ankara Üniversitesi Adresli: Evet

Özet

Discovery of novel anticancer drugs which have low toxicity and high activity is very significant area in anticancer drug research and development. One of the important targets for cancer treatment research is topoisomerase enzymes. In order to make a contribution to this field, we have designed and synthesized some 5(or 6)-nitro-2-(substitutedphenyl)benzoxazole (1a-1r) and 2-(substitutedphenyl)oxazolo[4,5-b]pyridine (2a-2i) derivatives as novel candidate antitumor agents targeting human DNA topoisomerase enzymes (hTopo I and hTopo II alpha). Biological activity results were found very promising for the future due to two compounds, 5-nitro-2-(4butylphenyl)benzoxazole (1i) and 2-(4-butylphenyl)oxazolo[4,5-b]pyridine (2i), that inhibited hTopo II alpha with 2 mu M IC50 value. These two compounds were also found to be more active than reference drug etoposide. However, 1i and 2i did not show any satisfactory cyctotoxic activity on the HeLa, WiDR, A549, and MCF7 cancer cell lines. Moreover, molecular docking and molecular dynamic simulations studies for the most active compounds were applied in order to understand the mechanism of inhibition activity of hTopo II alpha. In addition, in silico ADME/Tox studies were performed to predict drug-likeness and pharmacokinetic properties of all the tested compounds.