2. Academic Validation
  3. Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination

Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination

  • Eur J Med Chem. 2019 Aug 1:175:162-171. doi: 10.1016/j.ejmech.2019.05.006.
Katarzyna Piechowska 1,  Marta Świtalska 2,  Joanna Cytarska 1,  Karol Jaroch 3,  Kamil Łuczykowski 3,  Joanna Chałupka 4,  Joanna Wietrzyk 2,  Konrad Misiura 1,  Barbara Bojko 3,  Stefan Kruszewski 5,  Krzysztof Z Łączkowski 6
Affiliations

Affiliations

  • 1 Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.
  • 2 Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wrocław, Poland.
  • 3 Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.
  • 5 Medical Physics Division, Biophysics Department, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jagiellońska 13, 85-067, Bydgoszcz, Poland.
  • 6 Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland. Electronic address: [email protected].
PMID: 31082763 DOI: 10.1016/j.ejmech.2019.05.006
Abstract

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of Cancer cell lines via Caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) Cancer cell lines, with IC50 values of 5.43-11.06 μM. The lead compound 3g increases Caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high Tyrosinase inhibitory activity. The lead compounds 3g and 3h showed Tyrosinase inhibition effect, with IC50 values 3.22 and 3.51 μM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC50 72.27 μM) and 120 times higher than activity of ascorbic acid (IC50 386.5 μM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead Anticancer drug candidates.

Keywords

Antiproliferative activity; Caspase; Mushroom tyrosinase; Thiazole; Tropinone.

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