No abstract

The work reported the design and cytotoxic screening of synthetic small molecules: carbonitriles 3a-c, carboximidamides 4a-c, and oxadiazoles 5-19 as antitumor molecules. Molecules 4c, 9, 12, and 14 show promising cytotoxicity profiles against two cell lines higher than prodigiosin (PG). The results of topoisomerase enzyme inhibition assay show that carboximidamide 4c and oxadiazole 14 display potent inhibitory activity in nano-molar concentration higher than PG. In addition, carboximidamide 4c and oxadiazoles 9, 12, and 14 exhibit antiproliferative activities over MCF-7 cells by cell cycle arrest at G 1 phase and apoptosis inducing activity by increasing cell population percentages at pre G 1 and G 2 /M phases as shown by DNA-flow cytometry assay and annexin V analysis. Moreover, measurement of p53 and cell death mediators, show that carboximidamide 4c and oxadiazoles 9, 12, and 14 significantly up-regulate p53, Puma and Bax/Bcl-2 ratio levels. Subsequently, pro-apoptotic activities are confirmed by active caspase 3/7 percentages green fluorescence assay.

No abstract

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 17 against both HepG2 and HepG2-R cell lines. Among the target compounds, 14a (R-isomer) and 14b (S-isomer) displayed potent anti-proliferative activity against both HepG2 and HepG2-R cell lines in comparison to the reference drug erlotinib. Remarkably, compound 14a 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 14a (estratetraene core) exhibited a twofold increase in anti-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 14a and support further investigations to combat multidrug resistance in chemotherapy of hepatocellular carcinoma patients.