Date of Award:

5-2010

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Advisor/Chair:

Cheng-Wei Tom Chang

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.

Comments

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

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