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Abstract
Chapter one discusses the need to increase the chemical diversity in small molecule libraries and the underrepresentation of hydroxylamines in drug discovery due to weak heteroatom-heteroatom bonds, electrophilic and mutagenic properties. The N,N,O-trisubstituted-hydroxylamine functionality, however, stands out due to its low basicity, relative stability at ambient temperatures, and stability towards acetylating and sulfonylating enzymes. It has been found that N,N,O-trisubstituted-hydroxylamines can replace stereogenic centers in drug discovery while retaining the biological activity. At the outset of this project there was no direct approach for preparing complex N,N,O-trisubstituted hydroxylamines.Chapter two introduces a novel synthesis method for N,N,O-trisubstituted-hydroxylamines utilizing 2-methyltetrahydro-2H-pyranyl monoperoxyacetals as “R-O+” electrophiles. This method was applied to synthesizing nineteen diverse N,N,O-trisubstitutedhydroxylamines and is generally applicable for a wide range of magnesium amide nucleophiles along with simple and complex alcohol-derived peroxides. This method has the potential to serve as the basis for novel fragment-based compound libraries when coupled with previous work establishing the hydroxylamine functionality as a valuable isostere in drug discovery.
Chapter three presents a novel attempt at synthesizing O-glycosyl-N,N-disubstituted-hydroxylamines via acid-catalyzed rearrangement of N-glycosyl amine oxides. When 1,2-anhydro sugar donors were used for the glycosylation of N,N-disubstituted-hydroxylamines, the kinetically favorable glycosylamine-N-oxide was formed, which was then rearranged to the thermodynamically stable O-glycosyl-hydroxylamine. In this project, the influence of the substitution pattern on rearrangement was also evaluated. This method provides access to the N,N-disubstituted O-glycosyl-hydroxylamines.
Chapter four describes the design and synthesis of a hydroxalog of a known kinase inhibitor FRAX-1036 to evaluate the N,N,O-tri-substituted-hydroxylamines’ aptitude of reducing basicity and pKa, and eventually reducing toxicity. Inhibition studies for pak1 kinase and its close congeners demonstrated that the hydroxalog retained original nanomolecular activity while displaying 10-fold reduction of hERG inhibition while increasing lipophilicity at pH 7.4.
Chapter five details the synthesis of three novel kaempferol 3-O-rhamnopyranosides and their inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA). Differently protected thiorhamnosyl donors were synthesized and used in the glycosylation with a literature precedent 5,7,4’-tri-O-benzyl-kaempferol acceptor by the activation of N-Iodosuccinimide and trifluoromethanesulfonic acid, for the first time in this kind of flavanol glycoside synthesis.