Laboratory of Clinical Virology, Medical School, University of Crete, Voutes, Heraklion 71003, Crete, Greece.
Oncol Rep. 2018 Feb;39(2):519-524. doi: 10.3892/or.2017.6116. Epub 2017 Nov 28.
In the present study, the synthesis and biological evaluation of one novel pyridine and one novel pyridone anticancer compound is reported. The compounds 6‑(2,4‑dimethoxyphenyl)‑4‑(3,4‑methylenedioxyphenyl)‑1H‑pyridin‑2‑one (1) and 2‑(2,4‑dimethoxyphenyl)‑4‑(3,4‑methylenedioxyphenyl)pyridine (2) were synthesized from a chalchone precursor. 1 was more active than 2 in inhibiting the proliferation of MCF‑7 and HepG2 cells, whereas HepG2 cells were more sensitive to the antiproliferative activity of these compounds compared with MCF‑7 cells. The lowest IC50 value was noted for compound 1 in HepG2 cells (IC50=4.5±0.3 µM). The mechanism of action involved induction of G2/M arrest and apoptosis. Both 1 and 2 further induced downregulation of the cell cycle‑associated protein cyclin D1 and upregulation of the cell cycle inhibitors p53 and p21 and the apoptosis‑associated protein JNK in HepG2 cells. Compound 1 was further shown to induce phosphorylation of JNK in HepG2 cells. These results demonstrate promising cytostatic effects for the two novel anticancer compounds in human cancer cells.
在本研究中，报道了一种新型吡啶和一种新型吡啶酮抗癌化合物的合成和生物学评价。化合物 6-（2,4-二甲氧基苯基）-4-（3,4-亚甲二氧基苯基）-1H-吡啶-2-酮（1）和 2-（2,4-二甲氧基苯基）-4-（3,4-亚甲二氧基苯基）吡啶（2）由查尔酮前体合成。1 在抑制 MCF-7 和 HepG2 细胞增殖方面比 2 更有效，而与 MCF-7 细胞相比，HepG2 细胞对这些化合物的抗增殖活性更敏感。在 HepG2 细胞中，化合物 1 的最低 IC50 值为 4.5±0.3 µM。作用机制涉及诱导 G2/M 期阻滞和细胞凋亡。1 和 2 进一步诱导细胞周期相关蛋白 cyclin D1 的下调以及细胞周期抑制剂 p53 和 p21 和凋亡相关蛋白 JNK 在 HepG2 细胞中的上调。化合物 1 进一步显示在 HepG2 细胞中诱导 JNK 的磷酸化。这些结果表明这两种新型抗癌化合物在人类癌细胞中具有有前途的细胞抑制作用。
