Design, synthesis and potent anti-pancreatic cancer activity of new pyrazole derivatives bearing chalcone, thiazole and thiadiazole moieties: gene expression, DNA fragmentation, cell cycle arrest and SAR.

Abstract

Less than 5% of pancreatic cancer patients survive for more than five years after diagnosis. Therefore, there is an urgent need for novel therapeutic drugs to treat pancreatic cancer. Herein, we report the synthesis and full characterization of fifteen novel pyrazole derivatives bearing chalcone (4-10), thiazole (16-19) and thiadiazole (23-26) moieties. All the newly synthesized pyrazole derivatives were tested in vitro as anti-cancer agents against pancreatic cancer (PaCa-2), breast cancer (MCF-7), prostate cancer (PC3), and normal cell lines (BJ1). Three pyrazolyl-chalcone derivatives (4, 5, and 7) and a pyrazolyl-thiadiazole derivative (25) showed potent anti-cancer activity against the PaCa-2 cell line with IC50 values of 13.0, 31.5, 24.9, and 5.5 μg mL-1, respectively, compared with doxorubicin (IC50 = 28.3 μg mL-1). Compound 25 showed potent anti-cancer activity against the PC3 cell line with an IC50 value of 11.8 μg mL-1. In contrast, compounds 4, 5 and 7 are safer against the normal human-cell line (BJ1) with IC50 values of 74.2, 76.6 and 81.1 μg mL-1, respectively, compared with compound 25, which has an IC50 value of 23.7 μg mL-1. The mechanism of action of compounds 4, 5 and 7 against pancreatic cancer cells was studied by investigating gene expression, DNA fragmentation, comet assay and flow cytometry experiments using doxorubicin as a reference drug. Moreover, the structure-activity relationship between the structures of these compounds and their biological properties was discussed.