The endocannabinoid system and the de novo ceramide synthesis pathway as targets for the development of new anticancer and anti-neurodegenerative agents

Apoptosis is programmed cell death and this events represent an important biological target in development of anticancer and anti-neurodegenerative drugs. The main effector of this biochemical event is ceramide. Increased levels of this sphingolipid enhances apoptotic cell death allowing to reduce tumor growth. On contrary decreased ceramide levels reduce apoptotic events avoiding uncontrolled neurons death (anti-neurodegenerative effect). Ceramide levels can be modulated directly interfering on biological pathway responsible of its production and degradation or indirectly having effects on others endogenous system which are able to stimulate/inhibit ceramide mediated apoptosis. During my PhD both strategies has been pursued for the development of anticancer and anti-neurodegenerative drugs targeting the de novo synthetic pathway of ceramide and targeting the endocannabinoid system. A direct modulation of ceramide levels might be obtained by inhibition of an pivotal enzyme involved in the de novo ceramide pathway: serine palmitoyltransferase (SPT). Reduction of ceramide levels by SPT inhibition might represents a new therapeutic approach against neurodegenerative diseases caused by elevated levels of ceramide. Indirect modulation of ceramide levels (through activation of TNF or de novo biosynthetic pathways) by endocannabinoids receptor activation or MAGL inhibition represent a powerful tool in struggle against cancer. Moreover selective stimulation of CB2 receptor leads to antinflammatory effects which reduce neurodegenerative events. As previously defined my PhD research has been focused on targeting the endocannabinoid system (Section 1) and the de novo synthetic pathway of ceramide (Section2). In particular different goals has been pursued and reported in this thesis: SECTION 1. Targeting the endocannabinoid system •Design and synthesis of [18F]-labelled nitrogen heterocyclic derivatives as new candidate for cannabinoid CB2 receptor PET imaging •Assessment of a high-performance liquid chromatography assay for human recombinant monoacylglycerol lipase activity SECTION 2. Targeting the de novo ceramide synthesis pathway •Design, synthesis and biological evaluation of new SPT inhibitors •Development and optimization of an HPLC-FL method to screen SPT inhibitors •Evaluation and characterization of bacterial SPT inhibitors •An insight into bacterial SPT