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Issue Date: 5-May-2011
Authors: Grillo, Antonino
Title: Design and synthesis of new vinca alkaloid derivatives as potential sigma-2 receptor ligands
Abstract: Sigma-2 receptors are highly expressed in the motor regions of the brain, with an involvement in the motor coordination control and in the mediation of the typical anti-psychotics drugs side-effects.1 Moreover, sigma-2 receptors, were found overexpressed in tumor cells, and their activation with selective sigma-2 ligands, such as the alkaloid ibogaine, provides cellular death via apoptosis mechanism.2 In order to identify a new sigma-2 scaffold, existing in nature, a structural homology study was carried out. Vinca minor alkaloids were found to possess the structural requirements useful for sigma-2 receptor recognition. Indeed, vincane and vincamone structures, minimized with the software MOE, were overlaid to the minimized ibogaine structure, resulting in an optimal superimposition. Starting from vinca alkaloids, as natural templates, first aim of this work was to design different series of selective vinca-based sigma-2 ligands. Proper modifications were chosen in order to evaluate the requirements for sigma-2 binding affinity. Then the main issue was to elaborate an opportune synthetical strategy leading to a high regioselectivity in aromatic substitution reactions, in order to complete the synthetic pathway through the development of cross-coupling reactions, never described on this scaffold. Substitution reactions on vincane resulted in low yield and scarce regioselectivity. Instead, vincamone, used as starting material in the nitration reaction, produced quantitative yield and higher regioselectivity. In fact, only two isomers were easily obtained, 11-nitro vincamone (60% of yield) and 9-nitro vincamone (23% of yield), which were employed to achieve two different series of final products.3 The subsequent obtainment of iodio-vincamone derivatives has permitted to carry out Pd catalyzed reactions, such as Suzuki and Sonogashira.4,5 Thanks to this approach 6 new vinca based derivatives were synthetized and characterized. Regarding the pharmacological evaluation of the considered compounds, at the moment only some preliminary data on sigma-1 receptors is available.The vinca lead compounds and compound (13) have shown a sigma-1 Ki higher than 1000 nM. So far these results are in agreement with the predicted selectivity profile because the assessed compounds show scarce affinity for sigma-1 sites. However, I need data from a more extensive binding assay at sigma-2 sites to verify the predicted sigma-2 affinity and sigma-2 versus sigma-1 selectivity profile of the obtained vinca derivatives. Hence, in my research work, I designed and synthesized new potential sigma-2 ligands aiming to improve the knowledge about sigma-2 receptors and to develop useful drugs for different therapies. In fact, it is widely known that sigma-2 agonist could be employed in the cancer treatment and as biomarkers in tumor diagnosis, whereas the antagonist could avoid the motor disorders of the typical anti-psychotics drugs.
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