## 4 Discussion
In sharp contrast, the 4\({}^{\prime}\)-trifluoromethylomethyl phenyl derivative **9** (i.e., strongly electron-withdrawing again) is among the most efficient chelating agents under the majority of pH conditions studied. This discrepancy, together with the assumption that chelate formation should generally be supported by electron-rich ligands, strongly suggests that the electronic properties of the substituents on the C(9) phenyl have no direct impact on iron chelation. Their influence on other, no less important factors, such as the solvation of the resultant iron complexes, is probably of much higher significance. Similar to chelation, copper reduction with concomitant oxidation of the xanthones to \(o\)-quinones should also be facilitated by electron-rich ligands. In other words, electron-donating substituents should facilitate an electron transfer to Cu\({}^{2+}\). However, no straightforward relationship between the electronic properties of the substituents and the ability of the respective xanthone to reduce Cu\({}^{2+}\) can be found, either. For example, the 4\({}^{\prime}\)-trifluoromethylomethyl phenyl derivative **9** is the most active compound at pH 4.5-6.8, while the 2\({}^{\prime}\)-chloro-6\({}^{\prime}\)-fluoro phenyl compound **12** is the least effective at neutral and  
Figure 9: Energy minimization of the 4\({}^{\prime}\)-trifluoromethylomethyl phenyl derivative 9 by MM2 force field method. mildly basic pH values (6.8 and 7.5). Another C(2\({}^{\prime}\))-substituted phenol, substance **2**, appears to be among the least active compounds as well. Of note, all the **2**, **9** and **12** compounds have substituents with -I (withdrawing) effects. Therefore, factors (solvation) other than the electronic effects of the substituents are more important in copper (II) reduction. In the second part of this study, we selected the most potent compound **9** and tested its suitability for possible future in vivo studies. Our initial assumption, based on the above results, was that iron- and copper-reducing effects can be convenient for a chelator designed for cancer treatment, rather than for metal overload conditions. This speculation seemed to be supported by two arguments: (1) tumors are formed by rapidly growing cells, which require large intakes of iron/copper, and hence are also more susceptible to the iron/copper-based production of ROS via the Fenton chemistry. Increased ROS production with subsequent cellular death can be facilitated by weak chelators, which reduce iron/copper [15; 17; 34]. Indeed, out of our compounds, derivative **9** in particular was the most potent copper reductant in this study. (2) In addition to their metal-chelating effects, this series of xanthones possessed antiplatelet effects [28], and, according to novel investigations, activated platelets increase cancer cell survival and contribute to metastasis [35; 36]. Indeed, our group has recently demonstrated the solid potential of these compounds to destroy cancer cells in a variety of tumor cell lines. In particular, the most active metal-chelating and -reducing compound from this study--the trifluoromethyl derivative (**9**)--was also the most potent antiproliferative compound [23]. In order to expand this knowledge, we selected a breast cancer line together with the corresponding resistant alternative, since we had not included such a line in our previous experiments. Very surprisingly, **9** was about 30-200 times less potent in the selected cancer cell line, compared to its effect on cervical, colorectal, hepatocellular and alveolar adenocarcinomas. The difference between the fulvestrant-sensitive and -resistant cancer lines was relatively low (about twofold). Although the explanation for such a huge discrepancy is unclear, our experiments demonstrated that our theoretical assumption was not correct. While the cytotoxicity of the most active compound (**9**) was observed, the same compound was able to eliminate the cytotoxicity of copper against erythrocytes and conventional cancer cells.