Azaaporphines: Creating A Novel Subclass of Aporphine Alkaloid Derivatives



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Aporphine are a class of alkaloids that share a distinguishing rigid tetracyclic ring structure. While analogs of this class are found as natural products in a variety of different plant families, others are derived synthetically by researchers enticed by their broad biological properties. Properties ranging from being anti-cancer agents to treatment of advanced stage Parkinson’s disease. Hundreds of these alkaloids have been isolated and tested, however, there are no known examples of an aporphine which has a pyridine incorporated into its framework: an azaaporphine. After identifying two key intermediate compounds, we utilized a previously established reaction scheme to synthesize these stepping stones toward our final product. We have acquired and isolated these two intermediate compounds to construct the tetrahydroisoquinoline structure required for the final phenol arylation reaction that gives us an azaaporphine. Concurrently, we ran ligand similarity search within the Protein Data Base (PDB) to reveal potential biological targets of azaaporphines. We found that the enzyme phosphodiesterase 10A (PDE10A) has reported inhibitors similar to our compounds so we ran molecular docking simulations against it. This allowed us to determine binding affinity and several interactions between the enzyme and our compounds, revealing that PDE10A is a potential target of azaaporphines. In establishing the synthetic methodology of azaaporphine alkaloids, we are creating a novel sub-class of compounds with distinct properties and trailblazing a new pathway for others to explore and employ azaaporphines in new discoveries.