The uncontrolled genetic expansion of poly (L-glutamine) segments (with disease onset at >35 repeat units) has been associated with a number of neurodegenerative diseases classified as poly(Q) diseases. In order to understand the role and behavior of these expanded poly(L-glutamine) segments, synthetic techniques must be developed that allow for their synthesis with strictly controlled polymer chain lengths, mimicking healthy and abnormal poly(L-glutamine) segments. Ring-opening polymerizations of amino acid N-carboxyanhydrides (NCA), yield poly(amino acid)s with strictly controlled chain lengths (via the monomer-to-initiator ratio) as the reaction conditions can be adjusted to achieve living polymerizations.
However, a direct synthesis of poly(L-glutamine) using this approach proofed to be unfeasible (unpublished data). Hence, the research presented here focused on designing and developing a robust synthetic protocol to synthesize poly(L-glutamine) with 10 to 40 repeat units using polymer analogous conversions. The synthesis of poly(L-glutamine) was achieved through the controlled ring-opening polymerization of γ-benzyl-L-glutamate NCA initiated by an amino-terminated initiator. The resulting polymer was deprotected with Trimethyl silyl iodide to generate the free acid in the terminal side groups, which proved to be crucial for the final amidation reaction yielding poly(L-glutamine). Urea was used throughout the NCA ring-opening polymerizations to suppress beta-sheet formation in the initial phase of the polymerization. Furthermore, solvents and reaction temperature were set to maintain living polymerization conditions. This talk will provide insights into the synthesis and subsequent characterization of well-defined poly(L-glutamine).

Systemic illustration of overall synthetic steps and organic reactions to synthesize poly(<i>L</i>-glutamine)

Systemic illustration of overall synthetic steps and organic reactions to synthesize poly(L-glutamine)

Carmen Scholz

Univ. of Alabama in Huntsville

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