Synthesis of Modified Isoorotic Acid Nucleobases to Compare Pi-stacking and Hydrogen Bonding Interactions in PNA:RNA2 Triple Helix Formation
Student Research Paper
Chemistry and Biochemistry
Dr. James MacKay
Coding RNA has been studied extensively, yet comprises only 2% of transcribed DNA, leaving a vast amount of non-coding RNA virtually unexplored. Peptide nucleic acids (PNAs) are excellent biotechnological molecules that allow for exploration of RNA structure and function. This project focuses on comparing the binding affinity of hydrogen bonding and pi-stacking interactions within nucleobase modified PNAs to target double-stranded RNA (dsRNA) sequences through triple helix formation. Hydrogen bonds are favorable dipole interactions between an acidic proton and another electronegative atom, and pi-stacking interactions result from electronic stacking of electron-dense and electron-poor sections in aromatic rings. Synthesis of previous extended nucleobases involved the alkylation of isoorotic acid, followed by coupling to an amino-containing arene such as 3-amino-2-pyrazinecarboxamide, where the carboxamide provides a proposed third source of hydrogen bonding. The pi-stacking control designed in this project lacks the carboxamide while retaining the aromatic pyrazine. It is hypothesized that the 2-aminopyrazine PNA monomer will produce similar binding affinity to the 3-amino-2-pyrazinecarboxamide monomer and once incorporated into PNA will be tested for RNA binding. Pi-stacking will be further explored using 2,3,4,5,6-pentafluoro arenes as the fluorine atoms draw electron density from the aromatic ring allowing for potential stacking with electron-rich anilines.
Hess, Kyle, "Synthesis of Modified Isoorotic Acid Nucleobases to Compare Pi-stacking and Hydrogen Bonding Interactions in PNA:RNA2 Triple Helix Formation" (2021). Summer Scholarship, Creative Arts and Research Projects (SCARP). 52.
Scholarship, Creative Arts, and Research Project (SCARP)