Carbohydrate analogues of antitumor agents

This dissertation describes the synthesis and biochemical study of analogues of two known antitumor agents, bleomycin and SL0101. Bleomycin is a clinically useful chemotherapeutic agent that is known to derive its therapeutic effects through the sequence-selective degradation of DNA and possibly RNA. Conversely, SL0101, a kaempferol glycoside that was recently isolated from Forsteronia refracta, was found to possess enzyme-specific inhibitory activity against a small family of 90-kDa ribosomal 6S kinases (RSKs) known to be overexpressed in ~50% of human breast cancers. While these agents share little in common from a structural or biochemical standpoint, they each exist as fascinating probes of the roles of nucleic acids and proteins in cancer therapy.;Chapter 1 serves as a brief introduction to the interactions of small-molecule antitumor agents with nucleic acids and proteins. Specifically, agents that interact with DNA are divided into groups based on their known mechanism of action. In a similar manner, inhibitors of signal transduction pathways are identified according to their interactions with specific enzymes. Emphasis is placed on those antitumor agents that incorporate a carbohydrate moiety as a prominent structural feature.;Chapter 2 describes the synthesis and biochemical study of ten novel analogues of bleomycin. It was recently found that analogues of bleomycin containing a carbohydrate residue are able to effect the oxidative and hydrolytic cleavage of various RNA substrates in vitro, while analogues of deglyco bleomycin failed to cleave RNA in an oxidative manner. In an attempt to further define this mechanistic disparity, analogues of threonine bearing a variety of mono- and disaccharides are synthesized and incorporated into bleomycin by solid phase synthetic techniques. Further, a novel, iterative strategy for the synthesis of the natural disaccharide moiety of bleomycin is described.;The final chapter describes the synthesis of carbohydrate analogues of SL0101. Our understanding of the interactions of SL0101 with the protein kinase RSK is currently underdeveloped. Analogues are designed and synthesized in an attempt to further probe the functional importance of the L-rhamnopyranose moiety. Preliminary results of biochemical testing permit conclusions to be drawn regarding the intermolecular interactions of SL0101 and RSK.