| Summary: | A new series of nitric oxide-releasing estra-1,3,5,16-tetraene analogs (NO-∆-16-CIEAs) was designed and synthesized as dual inhibitors for EGFR and MRP2 based on our previous findings on estra-1,3,5-triene analog NO-CIEA <b>17</b> against both HepG2 and HepG2-R cell lines. Among the target compounds, <b>14a</b> (<i>R</i>-isomer) and <b>14b</b> (<i>S</i>-isomer) displayed potent <i>anti</i>-proliferative activity against both HepG2 and HepG2-R cell lines in comparison to the reference drug erlotinib. Remarkably, compound <b>14a</b> resulted in a prominent reduction in EGFR phosphorylation at a concentration of 1.20 µM with slight activity on the phosphorylation of MEK1/2 and ERK1/2. It also inhibits MRP2 expression in a dose-dependent manner with 24% inhibition and arrested the cells in the S phase of the cell cycle. Interestingly, compound <b>14a</b> (estratetraene core) exhibited a twofold increase in <i>anti</i>-proliferative activity against both HepG2 and HepG2-R in comparison with the lead estratriene analog, demonstrating the significance of the designed ∆-16 unsaturation. The results shed a light on compound <b>14a</b> and support further investigations to combat multidrug resistance in chemotherapy of hepatocellular carcinoma patients.
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