| Summary: | In the present paper, on the basis of molecular hybridization, a series of 4,6-dihydrazone pyrimidine derivatives containing the pyridine moiety were synthesized, structurally characterized, and evaluated in vitro for their antitumor activity. According to the results, all the tested compounds demonstrated broad-spectrum antitumor activity against selected tumor cell lines (MCF-7, BGC-823, A549, and BEL-7402) and no obvious toxicity toward normal cells HL-7702. In particular, compounds <b>10a</b> and <b>10f</b> were found to be the most promising antitumor agents among the tested compounds against BGC-823 cells (IC<sub>50</sub> = 9.00 μM and 7.89 μM) and BEL-7402 cells (IC<sub>50</sub> = 6.70 μM and 7.66 μM), respectively. Compounds <b>10a</b> and <b>10f</b> exhibited higher potency against BGC-823 and BEL-7402 than the positive control 5-FU (IC<sub>50</sub> = 15.18 μM and 15.81 μM). Further mechanism investigations demonstrated that compounds <b>10a</b> and <b>10f</b> could significantly increase the level of cellular ROS and induce early apoptosis of BGC-823 cells in a dose-dependent manner. Moreover, the DNA binding results from UV/Vis, CD spectroscopy, and molecular docking studies indicated that <b>10a</b> and <b>10f</b> bind with DNA via groove binding and partial intercalation. These results demonstrated that <b>10a</b> and <b>10f</b> may serve as novel lead compounds for the discovery of more dihydrazone pyrimidine derivatives with improved antitumor potency and selectivity.
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