Chemical Scaffolds based on Synthetic and Marine Derived Carboline Alkaloids for Targeting the Modulatory alpha+/beta site in GABAA receptors

Abstract

²-Carboline based chemical scaffolds are potential ligands for the ±+/² binding site of GABAA receptors. In particular, ²-carbolines belong to the ''ZK series'' such as ZK 91085 have been suggested to exert their second phase of action at the extracellular ±+/² interface. However, their chemical synthesis demand multi-step which prevents the access to large set of molecular libraries for neuropharmacological screening. In this regard, this FAPESP project intends to develop new synthetic route for ²-carboline scaffolds resembling the structural feature of ZK 91085. On the other hand, strategizing newer synthetic methods is of great importance not only for chemistry but also for various areas of science and technology. Especially, catalytic reaction would make the major part of this area that provides indispensable tools for transforming organic compounds to supply various important products to the society. In this regard, this FAPESP project intends to develop methodical synthetic approaches which grant access to biologically important synthetic and natural carboline alkaloids. In particular, the working principle of homogeneous gold catalyzed cycloisomerization of functionalized alkynes will be taken as an advantage to accomplish such objectives. Synthetic studies carried out in the proposed projects are expected to develop new methodologies/reagents to enhance the understanding of chemical-bonding, structure-reactivity and regiochemistry of gold catalysis and cycloisomerization reactions. It will also open new vistas for affording general strategies of obtaining natural product inspired compounds containing carboline cores. The expected impacts of the proposed methodologies are the discovery of alternative, highly innovative, pre-competitive strategies that lays the foundation for providing natural products and pharmaceutically important carboline leads. Not only ²-carbolines, but also the isomeric ³-carbolines are also feasible by the proposed synthetic route. Therefore, both ²- and ³-carboline libraries appropriate to target the modulatory ±+/² site in GABAA will be accomplished. As an extension of the developed approach, few marine alkaloids (such as Tiruchanduramine, Stolonine C, Variabine A and B) which are structurally closer to the synthetic carbolines is also possible. In view of additional candidates for biological screen, selected carbolines will be subjected to product diversification by operating C-H metalation reactionsvia turbo Grignard reagents. All the synthesized carbolines will be screened for pharmacological action against recombinant receptors. This would ensure the GABAA subtype efficacies for subsequent testing of top-ranked hits to predict their binding affinity. From a medicinal chemistry viewpoint, the carboline-based synthetic drugs proposed in this project might elicit novel and highly efficient neuropharmacological effects with no anti-targets. Hence, the proposed work may help to unfold new potent bioactive agents in disease areas. In summary, the present proposal facilitates to broaden the repertoire of catalytic gold chemistry to give synthetic chemists a larger selection of carboline products for rational and effective targeting of GABAA sub-types. The proposed concept not only solve issues associated with synthetic problems in the most effective way possible, but also bring strong impacts in the allied areas of chemical biology neuropharmacology. (AU)