Date of Award


Degree Type


Degree Name

Doctor of Philosophy



Major Professor

David C. Baker

Committee Members

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


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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