Synthesis Of 4'-O-Glycopyranosyl Paromomycin Aminoglycoside Antibiotics: Influence Of The Glycoside On Antiribosomal, Antibacterial Activity And Utilization Of Electrospray Ionization Mass Spectrometry To Evaluate Reactivity Of Glycosyl Phosphate
Open Access Thesis
Date of Award
The data in this thesis is trying to address two problems. The first problem is paromomycin associated ototoxicity; the second problem is the lack of precise reactivity data of glycosyl donors in one-pot synthesis.
Paromomycin is out of the market as an antibiotic due to its ototoxicity. Previous work done by Vasella and Böttger's groups identified 4'-O position of paromomycin as a promising site of modification to reduce the side effect. A series of 4'-O-glycopyranosyl paromomycin has been synthesized and tested for their biological activity and selectivity. From the results of anti bacterial ribosomal activity, anti hybrid ribosomal activity and antibacterial activity, it was found that 4'-O-4-amino-α-D-glucopyranosyl paromomycin is the most active among the sixteen 4'-O-glycosyl paromomycin derivatives synthesized. However, 4'-O-4-amino-α-D-glucopyranosyl paromomycin shows an inability to differentiate eukaryotic ribosomal A site from prokaryotic ribosomal A site. 4'-O-glycosyl paromomycin derivatives with equatorially oriented glycosidic bond at the 4'-O-glycosyl ring has more selectivity toward mitochondrial hybrid ribosomes than their corresponding derivatives with axially oriented glycosidic bonds. Therefore, it is promising to introduce an equatorially oriented substituent to the 4'-O position of paromomycin in the future drug design to reduce ototoxicity.
To evaluate the relative reactivity of glycosyl phosphate donors as a function of stereochemistry and protecting groups, electrospray ionization mass spectrometric fragmentation experiments were performed. Two methods to quantitatively access relative stability of glycosyl phosphates have been used: cone voltage fragmentation experiment and collision induced dissociation. Results from both methods showed that the α anomers of glucosyl phosphates are more stable than their corresponding β anomers regardless the protecting group. In the contrary, the α anomers of mannosyl phosphates are less stable than their corresponding β anomers irrespective with the protecting group. So it's likely glycosyl phosphates with the C1-dibutyl phosphate bond syn to the C2-H bond dissociate through a McLafferty rearrangement, but glycosyl phosphates with the C1-dibutyl phosphate bond anti to C2-H bond dissociate through an oxocarbenium ion. Cone voltage fragmentation experiment gave results contradicting the well-known benzylidene effect. Therefore, it seems the relative stability of glycosyl phosphates cannot reflect their relative reactivity in glycosylation reaction.
Chen, Weiwei, "Synthesis Of 4'-O-Glycopyranosyl Paromomycin Aminoglycoside Antibiotics: Influence Of The Glycoside On Antiribosomal, Antibacterial Activity And Utilization Of Electrospray Ionization Mass Spectrometry To Evaluate Reactivity Of Glycosyl Phosphate" (2014). Wayne State University Theses. 293.