Interaction of 2,6,7-Trihydroxy-Xanthene-3-Ones with Iron and Copper, and Biological Effect of the Most Active Derivative on Breast Cancer Cells and Erythrocytes

Abstract

Metal chelators can be potentially employed in the treatment of various diseases, ranging from metal overload to neoplastic conditions. Some xanthene derivatives were previously reported to complex metals. Thus, in a search for a novel iron or copper chelator, a series of 9-(substituted phenyl)-2,6,7-trihydroxy-xanthene-3-ones was tested using a competitive spectrophotometric approach. The most promising compound was evaluated in biological models (breast adenocarcinoma cell lines and erythrocytes). In general, substitution of the benzene ring in position 9 had a relatively low effect on the chelation. Only the trifluoromethyl substitution resulted in stronger chelation, probably via a positive effect on solvation. All compounds chelated iron, but their copper-chelating effect was only minimal, since it was no longer observed under highly competitive conditions. Interestingly, all compounds reduced both iron and copper. Additional experiments showed that the trifluoromethyl derivative protected erythrocytes and even cancer cells against excess copper. In summary, the tested compounds are iron chelators, which are also capable of reducing iron/copper, but the copper-reducing effect is not associated with increased copper toxicity.

Chromenol Derivatives as Novel Antifungal Agents: Synthesis, In Silico and In Vitro Evaluation

“…Cancerous MCF7/S0.5 cells, developed to grow in a low-sera environment, and non-cancerous HK-2 renal cells were used for these purposes. MCF7/S0.5 cells were cultivated as specified in our previous paper [ 70 ] and HK-2 cells were cultivated in high-glucose Dulbecco’s Modified Eagle Medium (DMEM) complemented with 10% FBS and 2 mM L-glutamine. The assay is based in the reduction in a tetrazolium salt which happens only in the mitochondria of viable cells.…”

Chelation of Iron and Copper by Quercetin B-Ring Methyl Metabolites, Isorhamnetin and Tamarixetin, and Their Effect on Metal-Based Fenton Chemistry

“…In the final step, the effect of both metabolites on copper-triggered red blood cell hemolysis was tested since copper, but not iron, is able to cause oxidative damage to erythrocytes . Interestingly, both compounds partly decreased the hemolysis, while isorhamnetin was unexpectedly more active (Figure ).…”

“…This assay was performed according to the previous studies − with some modifications. Blood samples were obtained from adult rats (Wistar Han, Velaz, s.r.o., Prague, Czech Republic) by exsanguination into heparinized tubes.…”

Dehydroflavonolignans from Silymarin Potentiate Transition Metal Toxicity In Vitro but Are Protective for Isolated Erythrocytes Ex Vivo

“…In the last step, the effect of both dehydroflavonolignans on the copper-based lysis of isolated rat red blood cells was assessed to see whether the in vitro data matched ex vivo experiments. Iron was not tested since red blood cells are generally not sensitive to iron, even at high concentrations [ 31 ]. Since direct, non-metal-related antioxidant effects can also protect erythrocytes, we also included silymarin and other flavonolignans isolated from silymarin ( Figure 11 ), which were previously shown to be unable to chelate copper and iron [ 24 ].…”

“…This methodology has also recently been reported [ 31 ]. Blood samples were obtained from adult rats (Wistar Han, Velaz, s.r.o., Prague, Czech Republic) by exsanguination into heparinized tubes.…”