Date of Award

12-2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

Michael D. Best, George K. Schweitzer, Jeffery M. Becker

Abstract

The tylophorine analogue, DCB-3503 (1-62b, NSC-716802), has been found to exhibit broad spectrum activity in vitro in the National Cancer Institute’s (NCI) panel of 60 human-derived cell lines. Recent studies involving HepG2, a human hepatocellular carcinoma cell line, and two pancreatic ductal carcinoma cell lines (PANC-1 and HPAC), have suggested that DCB-3503 (1-62b) exerts its unique growth inhibition properties by modulating nuclear factor kappa B activity as well as through the inhibition of nuclear protein synthesis. However, the physiologically relevant protein binding partner(s) of DCB-3503 (1-62b) have not been identified. Herein, the design and synthesis of two biotin conjugates of DCB-3503 are described. In both cases, attachment of the biotin moiety to the active core was achieved through a Cu(I)- catalyzed 1,3-dipolar Huisgen cycloaddition (“click”) coupling reaction. Additionally, 3D QSAR studies were performed using comparative molecular field analysis (CoMFA) on a set of phenanthrolizidine alkaloids with inhibitory activities against the HepG2 cell line. A satisfactory CoMFA model was obtained with LOO cross-validation q2 and noncross- validated r2 values of 0.567 and 0.935, respectively. The developed model demonstrated promising predictive abilities as discerned by the results of the external test set.

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