Date of Award:

5-2010

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Committee Chair(s)

Cheng-Wei Tom Chang

Committee

Cheng-Wei Tom Chang

Committee

Alvan C. Hengge

Committee

Bradley S. Davidson

Committee

Robert S. Brown

Committee

Jon Y. Takemoto

Abstract

Various anticancer and antibacterial agents have been synthesized via azide chemistry by taking advantage of carbohydrate. Starting from the synthesis of 14 glycosyl azides, a library of carbohydrate-oxazolidinone conjugates and a library of carbohydrate-cyclopamine conjugates with biological interests were synthesized based on a highly efficient "click reaction" assisted by sonication. Some of the conjugates have improved solubility and enhanced anticancer activity. A library of neomycin B derivatives with various modifications at the 5" position has been synthesized. Two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics and significant synergistic activities were observed. Three different classes of aryl N-glycosides have been synthesized by employing 1,4-naphthoquinone and glycosyl azides undergoing a [2+3] cycloaddition. Alkyl azides can also undergo the same cycloaddition. After the removal of the protecting group, a library of 9,10-anthraquinone derivatives with potential anticancer activity and a library of 2-aminomethylene-1,3-indanediones with novel antibacterial activity have been developed, respectively. A one-pot three-component [2+3] cycloaddition for the synthesis of 1-alkyl 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione and 2-alkyl 2H-naphtho[2,3-d][1,2,3] triazole-4,9-dione has been developed. By taking the advantage of their difference in basicity, both products can be obtained in good purity. Using an allylic azide rearrangement, a convenient method has been developed for the synthesis of several 2',3'-dideoxyaminoglycosides. The antibacterial activity of these novel aminoglycosides also confirms the indispensable role of the 2'-NH2 group for both neomycin and kanamycin classes of aminoglycosides. A novel structural motif containing the hexylaminocarbonyl groups at O-5 and/or O-6 of 2',3'-dideoxyneamine could lead to the production of new aminoglycosides against resistant bacteria.

Checksum

808cc955505490d684502e44ac6c09ed

Comments

This work made publicly available electronically on August 2, 2010.

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