Design of Small Molecules toward the Modulation of Molecular Biosystems

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Title: Design of Small Molecules toward the Modulation of Molecular Biosystems
Author: Basso, Anne
Advisors: Deiters Alexander, Committee Member
Melander Christian, Committee Chair
Novak Bruce M., Committee Member
Ghiladi Reza, Committee Member
Abstract: The design of small molecules toward the modulation of a specific molecular biosystem was explored in two distinctive parts: (PART A) Design of Carbocyclic Peptide Analogues to Counteract a Pre-Determined RNA-Protein Interaction, and (PART B) Design of Imidazole Derivatives toward Biofilm Modulation. The design of carbocyclic analogues was particularly relevant to RNA-protein interactions due to the ever-raising evidence of RNA's essential role in cellular functions and high affinity of cyclic peptides with oligonucleotides. A facile route toward the synthesis of carbocyclic heptapeptides counterparts of bTAR RNA cysteine-constrained peptide binders, P1 and P2, was developed through the exploration of ring-closing metathesis conditions with four metathesis catalysts (Grubbs 1st, 2nd and Hoveyda-Grubbs 1st, 2nd generations) on the (1) resin-free, and (2) resin-bound linear di-olefin precursors. Classic Fmoc chemistry was employed to generate the di-olefin precursors prior to cyclization. Optimum ring closing conditions for this crucial step were explored in order to generate the substantial 29-membered macrocyles, and the results of this study are described in PART A. The design of imidazole derivatives was particularly relevant toward biofilm modulation studies due to the ever-increasing number of untreatable biofilm-derived bacterial infections. Imidazole marine alkaloids were found to be great anti-biofilm agents particularly the 2-aminoimidazole scaffold that is embedded within the natural product bromoageliferin. Thus, we sought to explore further 2-aminoimidazole scaffolds to establish structure activity relationships and to provide insight on the mechanism behind the mysterious biofilm formation as entailed in PART B.
Date: 2008-08-18
Degree: MS
Discipline: Chemistry

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