Design and synthesis of new symmetrical derivatives of dihydropyridine containing a pyridyl group on the 3, 5-positions and evaluation of their cytotoxic and multidrug resistance reversal activity

Abstract

Abstract Today, chemotherapy is an important part in the treatment of several kinds of cancer; however, the development of drug resistance remains one of the major obstacles in successful chemotherapy. Several types of agents have been recognized as multidrug resistance (MDR) inhibitors, among which the 1,4-dihydropyridines (DHPs) have been investigated the most. P-glycoprotein inhibition has been reported as the main MDR reversal mechanism of DHPs, whilst other mechanisms such as inhibition of topoisomerase II have received less attention. Therefore, in this study new derivatives of DHP have been synthesized. Their cytotoxic activity and their effects in reversing atypical MDR have been evaluated. The results confirmed the appropriate effect of these compounds on atypical MDR. Although it was observed that these compounds had a moderate cytotoxic effect, the cytotoxicity of one compound on the K562 cell line (IC50 = 6.61 μM) was comparable with that of doxorubicin (IC50 = 4.17 μM). Finally, the Ca2+-channel antagonistic activity, an undesired effect for these compounds, was evaluated.