Abstract

Project I 2-Deoxystreptamine (2-DOS), the most conserved central scaffold of aminoglycosides, is known to specifically recognize the 5'-GU-'3 sequence step through highly conserved hydrogen bonds and electrostatic interactions within and without the context of aminoglycosides (Figure 1a). We proposed that a novel monomeric unnatural amino acid building block using 2-DOS as a template would allow us to develop RNA binding molecules with higher affinity and selectivity than those currently available. Conjugating two or more of the monomeric building blocks by an amide bond would introduce extra hydrogen bonding donors and acceptors that are absent in natural aminoglycosides and increase specificity of binding to a target RNA through a network of hydrogen bonds. In addition, the amide conjugation between the monomeric building blocks places two GU-base recognizing amines at 5 Å… distance, which is equal to the distance of neighboring base stacks in dsRNAs We hypothesized that targeting dsRNAs containing multiple consecutive 5'-GU-'3 sequence steps would become possible by connecting two or more of the monomeric building blocks by amide bonds. According to the proposed hypothesis, we designed three dimeric 2-DOS compounds connected by an amide bond. These three targets include the dimeric 2-DOS substrate connected by an amide bond, the dimeric 2-DOS containing the sugar moiety from Neamine, and a dimeric 2-DOS connected by a urea linker. These compounds were then tested for sequence specific binding against 8 different RNA strands, and for antibacterial activity against E. coli, actinobacter baumannii and klebsiella. Project II A dual optimization approach was used for to enhance the catalytic activity and chemoselectivity for nitro reduction. In this approach the composition of the nanoparticles and electronics effects of the polymer were studied towards nitro reduction. Bimetallic Ruthenium-Cobalt nanoparticles showed exceptional catalytic activity and chemoselectivity compared to monometallic Ruthenium nanoparticles. The electronic effects of the polymer also had a significant effect on the catalytic activity of the bimetallic nanoparticles. The electron-deficient poly(4-trifluoromethylstyrene) supported bimetallic nanoparticles undergo nitro reduction in 20 minutes at room temperature, whereas electron-rich poly(4-methylstyrene) and poly(4-methoxystyrene) supported bimetallic nanoparticles to longer reaction times to go to completion. Electronics of the polymers also effects the change in mechanism of nitroreduction. Polystyrene bimetallic Ruthenium-Cobalt nanoparticles showed excellent yields and chemoselectivity towards nitro functional group in the presence of easily reducible functional groups like alkenes, alkynes, allyl ethers, propargyl ethers. Monometallic ruthenium nanoparticles also showed excellent reactivity and chemoselectivity towards azide reduction in the presence of easily reducible functional groups. Interestingly monometallic ruthenium nanoparticles showed regioselective reduction of primary azides in the presence of secondary and benzylic azides, also aromatic azides can be selectively reduced in the presence of secondary azides. These polystyrene supported nanoparticles are heterogeneous and are easily separated from the reaction mixture and reused multiple times without significant of catalytic activity.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2015-06-01

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd7864

Keywords

Aminoglycosides, RNA binding studies, 2-DOS, Antibiotics, bimetallic nanoparticle, nitroarene reduction, polymer support, metal-support interaction

Included in

Chemistry Commons

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