Generation and validation of novel families of multi-target small molecules against glioblastoma

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults and is characterized by its high heterogeneity, which makes current treatments have limited efficacy. In this context, both indole-based and multitargeted compounds have emerged as potential strategies for the development of new drugs for the treatment of cancer, and in particular, GBM. In this PhD thesis, we generated four new families of indole-based multitargeted compounds by combining the tetratarget compound Contilisant with histone deacetylase (HDAC) inhibitors, synthesizing 30 compounds designed to inhibit HDACs, monoamine oxidases (MAOs), and cholinesterases (ChEs), as well as to modulate histamine H3 and sigma-1 receptors, whose expression is altered in GBM. Following an initial screening to select the most promising compounds for GBM, the six selected compounds were found to be capable of inhibiting HDACs, MAOs, and ChEs, and to have cytotoxic effects, promoting reduced proliferation and increased apoptosis in both GBM cell lines and glioma stem cells. Furthermore, further characterization of two of the compounds revealed that they both altered the cell cycle and synapse in glioma stem cells and reduced tumor growth in vivo.