Design of Small Molecules toward the Modulation of Molecular Biosystems

cyclic peptides;ring closing metathesis;biofilms;biofilm modulation;imidazoles

Basso, Anne ; Deiters Alexander, Committee Member,Melander Christian, Committee Chair,Novak Bruce M., Committee Member,Ghiladi Reza, Committee Member,Basso, Anne ; Deiters Alexander ; Committee Member ; Melander Christian ; Committee Chair ; Novak Bruce M. ; Committee Member ; Ghiladi Reza ; Committee Member

University:North Carolina State University

关键词: cyclic peptides;    ring closing metathesis;    biofilms;    biofilm modulation;    imidazoles;   

Others  :  https://repository.lib.ncsu.edu/bitstream/handle/1840.16/266/etd.pdf?sequence=1&isAllowed=y

美国|英语

来源: null

【 摘 要 】

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.