Design and synthesis of small molecules, polyamines, and N-acylated polyamines that affect biological systems

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The focus of this thesis is the design of non-natural molecules for use in biological applications. Chapter one details a strategy to use small molecules to reactivate mutated p53, an oncoprotein that is prevalent in several types of cancer, back to its wild-type function. Wild-type p53 has the ability to induce cell death upon DNA damage, thus mutant p53 reactivation could lead to novel cancer therapeutics. By simplifying the scaffold of PRIMA-1, a bicyclic small molecule reported to reactivate p53, we synthesized serine and diaminopropionic acid derived small molecules to examine their affect on mutant p53. Several of these molecules were found to halt the cell growth of R175H and D281G p53 mutant strains. The second chapter examines inhibition of HIV-1 transcription by the complexation of TAR RNA with a polyamine trimer (YYY) consisting of three tyrosine residues. The solid-phase synthesis of the polyamine was optimized with the use of a new resin linker, Fmoc-beta-homoalanine, which increased yield and purity. NMR studies confirmed the binding of YYY specifically and with moderate affinity to the bulge region of TAR RNA, the area critical for inhibition of transcription. Lastly, chapter three describes the synthesis of a functionally dense N-acylated polyamine scaffold to inhibit protein-protein interactions. Our multivalent platform can display side chains for molecular recognition at a density double that of natural peptides. Two parallel combinatorial libraries of these molecules were synthesized and screened for protein binding using quantum dot fluorescent technology. This strategy yielded a molecule that binds to the HIV-1 Vpr protein with a Kd of approximately 25 micromolar, and partially reversed Vpr expression in podocytes.

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  • 10/03/2018
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