Date of Award

12-1-2012

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry/Green Chemistry

First Advisor

Wei Zhang

Second Advisor

Manickam Sugumaran

Third Advisor

DeYang Qu

Abstract

Fluorescence imaging is a powerful tool that permits visualization of specific cell states with a population; however existing methods for fluorescence labeling cannot be easily applied in many biological systems. Unlike antibodies, small molecule probes can be cell permeable and therefore useful in live-cell and in vivo imaging experiments; moreover, small molecule probes do not require genetic manipulation of cells.

Protein kinases are ideal targets for the development of selective fluorescent small molecule probes in many ways. This is because protein kinases are involved in most cellular processes and changes in their localization, accessibility, and abundance are associated with changes in cellular state. In addiditon, drug discovery and chemical biology efforts have produced many selective, cell permeable small molecule ligands of specific cellular kinases.

Here we describe our initial attempts to leverage existing, well characterized kinase inhibitors to develop fluorescent small molecule probes for their usage as imaging tools in cancer biology. BODIPY conjugated kinase inhibitors of parent compounds, such as Mps-IN-1, Dasatinib, and BI2536, were synthesized; their inhibition ability and immunofluorescence staining were tested.

The N-O bond cleavage of isoxazole can produce multiple functional groups in one step and involves in the metabolism of isoxazole containing drugs. Herein, we report a new, simple and efficient method, palladium-catalyzed reaction under the closed system microwave irradiation in protic solvents, to cleave the N-O bond of isoxazole. It is also applied to a mimic metabolism process of Leflunomide®. Occasionally, N-N-benzyl rearrangement products were obtained instead of the produce of isoxazole ring opening in aprotic solvents.

One pot reaction of β-ketoesters, Selectfluor®, and various Michael acceptors including nitroolefins, chalcones, and maleimides, catalyzed by a novel cinchona alkaloid-based thiourea bifunctional organocatalyst generated fluorinated quaternary stereogenic centers adjacent to tertiary stereocenters. The catalyst could be recovered from the reaction mixture by fluorous solid-phase extraction (F-SPE) with excellent purity for direct reuse.

Comments

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