Part I. Vitamin B12 for targeted drug delivery. Part II. Fullerene derivatives as alpha-helix mimics

Part I. The thesis first describes the use of Vitamin B12 as a targeted delivery agent for anti-cancer drugs. Vitamin B12 is the essential enzyme cofactor for methionine synthesis, a limiting component in the production of folates, and an essential carbon source for the synthesis of nucleotides and DNA. Once absorbed by the body, vitamin B12 is transported to the blood stream where it is complexed with its carrier protein transcobalamin II (TCII). The B12/TCII complex is recognized and taken into cells by specific cell surface receptors that are overexpressed in rapidly dividing cells, forming the basis of a new anti-cancer strategy. The thesis will describe the synthesis of Vitamin B 12-drug conjugates, their ability to still bind strongly to TCII and cellular receptors, and preliminary results from biological studies in cells and animals.; Part II. Previously, a series of water-soluble C 60 derivatives was synthesized in the Wilson laboratory and shown to be active against the enzyme nitric oxide synthase. It is believed that these fullerene derivatives were acting as calmodulin antagonists. Calmodulin mediates many key enzymes by targeting basic amphiphilic alpha-helix regulatory domains. Furthermore, it has been known for years that many calmodulin antagonists are commonly hydrophobic amines. The previously reported amine derivatized fullerenes are amphiphilic in nature and led to the hypothesis they act as alpha-helix mimics. This hypothesis was tested by the synthesis of the carboxylic acid counterparts to these aminofullerenes and the comparison of their biological activity against nitric oxide synthase. In addition, non-amphiphilic bis-compounds of both C60 and C70 were synthesized to explore the effect that the shape and side-chain presentation have on this inhibition.