Screening of 1,2-furanonaphthoquinones 1,2,3-1H-triazoles for glycosidases inhibitory activity and free radical scavenging potential: an insight in anticancer activity

In many cancer cells, glycoproteins show abnormal glycosylation patterns which have been associated with tumor initiation, progression, and metastasis. Thus, the glycosidases involved in glycoprotein maturation represent good targets for the development of new anticancer agents. In a previous report, we synthetized and evaluated the cytotoxic effect of a novel series of nor-β-lapachone tethered to 1 H -1,2,3-triazoles (1,2-FNQT, 9a – r ) against a panel of leukemia cell lines. Many 1,2-FNQT were active at low micromolar concentration and some were selective for cancer cells rather than normal ones. These results prompted us to investigate the mechanism of action that underlies their cytotoxic effect. Here, we tested if this effect could be attributed to the inhibition of cancer-related glycosidase activities, namely α-glucosidase and α-mannosidase. To evaluate enzyme selectivity, the same compounds were screened on other glycosidases of physiological relevance. In addition, we also studied the free radical scavenging activity of 1,2-FNQT, since redox metabolism plays a part in cancer development. Overall, the compounds were weak glycosidase inhibitors at 500 µM. The most active was 9 i (IC 50 = 413.7 µM) for α-glucosidase activity. In contrast, many of the compounds decreased more than 40% the content of DPPH, a free radical reagent, at 500 µM. This reduction was positively correlated with 1,2-FNQT cytotoxic potency, but only in KG1 cells (acute myelogenous leukemia). In conclusion, the cytotoxic effect of 1,2-FNQT on leukemic cells does not seem to be related to glycosidases inhibition, but may be, at least in part, due to their free radical scavenging activity.