Synthetic approaches toward azabicyclic and azaspirobicyclic scaffolds relevant to peptide conformation control.
2009-12
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Synthetic approaches toward azabicyclic and azaspirobicyclic scaffolds relevant to peptide conformation control.
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2009-12
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A ring closing metathesis (RCM) strategy was explored toward synthesis of a conformationally constrained Type VIa #1;-turn mimic of the tripeptide dopaminergic receptor modulator, Pro-Leu-Gly-NH2 (PLG). It was anticipated that this strategy would result in a generalized route to synthesize the indolizidinone scaffold-based Type VIa #1;- turn mimic of any Xaa-Pro dipeptide. Although this strategy was unyielding in the desired result, the study highlighted the recalcitrant reactivity of sterically hindered amino acid residues. The interaction between the N-terminal tetrapeptide, Ala-Val-Pro-Ile (AVPI) of the pro-apoptotic protein, second mitochondrial activator of caspases (Smac), and the binding site on the X-linked inhibitor of apoptosis protein (XIAP) has been previously validated for its chemotherapeutic potential. We, designed and synthesized, conformationally-constrained diastereoisomeric AVPI analogues, containing the 5.5- fused bicyclic thiazolidine scaffold. Although the synthesis of this scaffold presented several challenges; the base- and acid-lability of the thermodynamically unstable diastereomer as well as difficulties in the vital amidation step notwithstanding; synthesis of one diastereomer was successfully completed. A diastereomeric pair of 5.6.5-azaspirobicyclic lactams, synthesized to mimic the biological activity of PLG and possessing opposite stereochemistry at the C-8a’ position, was recently found to have opposing dopamine D2 receptor modulatory activities. Our goal was to identify the structural elements in this scaffold that were responsible for this opposite activity. We therefore, utilized molecular modeling on existing PLG modulators containing this scaffold and designed more 5.6.5-azaspirobicyclic lactams containing: (1) different stereochemistry at the C-3’ position and (2) various substitutions at the C-2’ position. Following the established paradigm toward synthesis of the target molecules only led to inconvenient epimerization/racemization issues. However, with a seemingly simple change in the order of events provided the desired target molecules. In addition, our initial hypothesis was verified by pharmacological testing of the synthesized molecules. Eventually it is anticipated that use of both positive and negative modulators will serve to understand the overall structural and biochemical mechanism of PLGmediated D2 receptor modulation.
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UNiversity of MInnesota Ph.D. dissertation. December 2009. Major: Medicinal Chemistry. Advisor: Rodney L. Johnson.1 computer file (PDF); xxv, 232 pages.
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Bhagwanth, Swapna. (2009). Synthetic approaches toward azabicyclic and azaspirobicyclic scaffolds relevant to peptide conformation control.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/58178.
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