Synthesis of Dysiherbaine and Separase Inhibitors in Drug Development for Neural Disorders and Breast Cancer
Do, Ha T. 1986-
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Drug development has been playing an important role in the search for new medications for hard-to-treat diseases. The development of a new drug for a specific biological target mainly derives from two sources: natural products or small organic molecules. This dissertation presents our effort and accomplishments in the synthesis of the natural product dysiherbaine and small molecule inhibitors of the separase enzyme in drug development for neural disorders and breast cancer. Ionotropic glutamate receptors (iGluRs) are synaptic receptors that are involved in brain signaling mechanisms and are also implicated in neuronal disorders. Dysiherbaine, isolated from the marine sponge Dysidea herbacea, has shown high affinity and selectivity for certain iGluRs making it a unique ligand to explore the complexity of these receptors. In this dissertation, we present the synthesis of dyshiherbaine by using a novel approach that allows the modification of important functionalities and their stereochemistry at a late stage of the synthesis. The synthetic route was established by using an intermediate with a carbon-carbon double bond between C8 and C9 to which various functional groups can be added. To install the aminohydroxyl functional group at C8 and C9 with the correct stereochemistry as the natural product, dysiherbaine, the ring opening and rearrangement of the Boc-protected aziridine was utilized. Furthermore, our extensive study in constructing the amino acid side chain at C4, using an optimized condition for asymmetric hydrogenation was a key step to obtain the natural product. Additionally, a library of small molecule inhibitors of saparase enzyme was synthesized and utilized in a structure-activity relationship (SAR) study. Due to the overexpression of separase enzyme in human cancer tumor cells, modulation of separase enzymatic activity could constitute a new therapeutic strategy for targeting resistant, separase-overexpressing aneuploid tumors, particularly hard-to-treat triple negative breast cancer. Herein, we report the synthesis, structural information, and SAR of novel separase inhibitors based on structural modification on three main regions of the lead molecule (2,2-dimethyl-5-nitro-2H-benzimidazol-1,3-dioxide). Various functional groups have been used to attach to the three modified regions and general trends have been observed on the effects of the substituting functionality. Our calculation and bioassay results indicate that the oxides on the lead compound could possibly be the binding site to separase enzyme.