Discovery and optimization of anthraquinone derivatives containing substituted bisbenzyloxy groups as a novel scaffold damaged endoplasmic reticulum and against hepatocellular carcinoma cells.

[Display omitted] • Anthraquinone derivatives containing substituted with donor electrons bisbenzyloxy groups can further enhance ERS. • Compound KA-MO-g damaged ER, resulting in dysfunction and inadequate synthesis of glycoproteins and disulfides. • Compound KA-MO-g killed liver cancer cells mainly through damaged endoplasmic reticulum then inducing apoptosis. This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound KA-MO-g showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound KA-MO-g simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload, then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because KA-MO-g showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study. [ABSTRACT FROM AUTHOR]