Design, synthesis and in vitro evaluation of novel dehydroabietic acid derivatives containing a dipeptide moiety as potential anticancer agents

• Synthesis of a range of novel DHA-dipeptide derivatives is described.
• In vitro anticancer and noncancerous screening for all the targeted compounds.
• Compound 8k blocked the HeLa cell cycle at S phase and induced the apoptosis of this cell.

A series of novel dehydroabietic acid (DHA) chiral dipeptide derivatives were designed and synthesized as potent antitumor agents. The inhibitory activities of these compounds against NCI–H460 (lung), HeLa (epithelial cervical) and MGC-803 (gastric) human cancer cell lines were estimated by MTT assay in vitro. The antitumor activities screening indicated that many compounds showed moderate to high levels of antitumor activities against these three cancer cell lines and most of these compounds displayed more potent inhibitory activities compared with commercial anticancer drug 5-fluorouracil (5-FU). The induction of apoptosis and affects on the cell cycle distribution with compound 8k were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay, flow cytometry and the activities of caspase-3 and -9 assay in Hela cells, which exhibited that the compound could induce cell apoptosis in Hela cells. In addition, further investigation showed that apoptosis were associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c release and intracellular ROS production, elevation of Bax expression, down-regulation of Bcl-2, and the activation of caspase-9 and -3.

A series of novel DHA-dipeptide derivatives (8–9) was designed and synthesized as antitumor agents. Representative compound 8k blocked the HeLa cell cycle at S phase and induced apoptosis of this cell through mitochondrial pathway.Figure optionsDownload as PowerPoint slide