# Xanthone Derivatives in the Fight against Glioblastoma and Other Cancers
## 1 Introduction
### Characteristics of Medicinal Chemistry Research Regarding Brain Cancers  
Glioblastoma multiforme (GBM) is the most frequent, primary malignant, lethal brain tumor in humans, characterized by a survival rate of less than 5% in 5 years after diagnosis, as well as a median survival of 14.6 months. Notwithstanding the considerable advancement in the development of new treatments, this disease continues to progress through rapid cell growth [15]. Like most tumors, this disease is treated by surgical resection followed by radiotherapy and chemotherapy (Temozolomide). However, the distribution of the drug to the tumor is also a challenge, resulting in poor efficacy. Treatment for brain glioma is still insufficient, and there is an urgent need for new agents against glioblastoma with strong brain permeability [16]. Currently, despite significant progress in therapy for cancers, human brain tumors still require unmet medical needs, to such an extent that even dietary phytochemicals are considered a possibility for any therapy or even to serve as lead compounds in the process of drug discovery [12]. A great number of epidemiological studies have proven the chemo-preventive role of natural, dietary compounds against cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach to the effective treatment of cancer [17]. Effective treatment for brain cancer would have a large impact on this cancer's morbidity and mortality. Accordingly, new derivatives have been synthesized that are based on the structures of the active compounds that have been isolated from plants. The xathone skeleton is nowadays seen as a privileged structure [18] and several xanthone derivatives have reached the stage of clinical trials, e.g., Gambogic acid [19] (chapter 2.2 Figure 3) and dimethylxanthoneacetic acid (DMXAA, 5,6-dimethylxanthone-4-acetic acid, Vadimezan) [20]. DMXAA is currently not associated with central nervous system tumors. However, it is worth mentioning in the context of research on xanthones in cancer therapy. It is a naturally occurring xanthone that has also been synthesized and described in the literature [18; 21; 22; 23; 24]. The compound belongs to vascular-disrupting agents. Its antitumor activity is probably based on the reduction of the blood flow within the tumor, causing vascular collapse and hemorrhagic necrosis--which consequently generates tumor hypoxia [20; 25; 26; 27; 28]. Vadimezan had been the subject of two big clinical trials (phase III) [20; 25; 29] regarding its efficacy in non-small cell lung cancer (NSCLC) in combination with Paclitaxel and Carboplatin or Docetaxel. Both trials were terminated prematurely due to a surprising lack of improvement in the overall survival levels when compared to the control group. The failure of the clinical trials could have been caused by the imperfection of the animal models, the selection of taxanes as the primary therapy, or the wrong choice of tumor type. Currently, the potential use of DMXAA in combination with immunotherapy has been proposed, due to the effectiveness of these drugs in different areas of tumor tissue [25]. Exploring unconventional molecular targets raises hopes for new anti-cancer therapies. There are numerous types of membrane receptors specific to various mitogens: (1) epidermal growth factor receptor (EGFR) responsive to EGF (epidermal growth factor) and TGF (transforming growth factor), and (2) platelet-derived growth factor receptors PDGFR-\(\alpha\) and -\(\beta\), (3) insulin-like growth factor receptor (IGFR). These cell structures may be involved in the stimulation of tumor cells via an alteration of signaling cascades that has already been described.