Tumor Targeting Moiety of the Antitumor Agent Bleomycin

This dissertation describes the synthesis and biological evaluation of compounds designed to investigate the tumor targeting properties of bleomycin; specifically the role of the carbohydrate domain. Bleomycin is a glycopeptide antitumor antibiotic that derives its therapeutic effect from inducing single and double stranded DNA, and possibly RNA, breaks. Although it is widely accepted that bleomycin shows a high proclivity for selected types of malignant tissue, adverse effects are still observed with its administration. The dose limiting toxicity of bleomycin is pulmonary fibrosis which is observed in ∼10% of patients. The origin of this toxicity was also examined.;Chapter 1 describes a brief summary of small molecule antitumor agents and the variety of mechanisms by which they induce their toxic effect, most notably bleomycin and its tumor cell selectivity. Additionally, it also serves to describe the diversity of carbohydrates in biological systems, specifically cell surfaces, and their critical role in extracellular communication.;Chapter 2 outlines the synthesis and purification of a diversity of bleomycin analogues that were selected to probe the relationship of individual structural features of bleomycin and their role in modulating pulmonary toxicity. These compounds were employed in an in vivo assay system and the results are summarized herein.;The third chapter describes the synthesis and biological evaluation of biotinylated bleomycin and bleomycin disaccharide analogues that enabled their conjugation to the surface of ultrasound contrast agents. These targeted microbubbles provide a platform through which direct visual observations can be made pertaining to potential interactions between bleomycin, and its disaccharide, and cell surface receptors.;The final chapter examines the synthesis and in vitro evaluation of fluorescently labeled bleomycin and disaccharide analogues. Fluorescence microscopy not only provides a more sensitive assay system to investigate the cellular recognition of bleomycin but also provides a method to directly observe cellular distribution of the reporter-labeled bleomycin; potentially providing additional information on its intracellular mechanism of action.