The goal of the proposed research is to understand the relationship between structure and function in three different families of glycosylated antitumor antibiotics by studying a prototypical molecule from each family. The selected molecules, calicheamicin, chromomycin, and aclacinomycin, bind to DNA and contain carbohydrate moieties that are known to be essential for activity. Nevertheless, they have different mechanisms of action. A better understanding of how structure and function are related in thee molecules could lead to the ability to design better antitumor agents. The proposed aims include two types of experiments: those directed towards understanding how the natural products themselves function; and those directed towards synthesizing and evaluating analogues of the natural products based on hypotheses about which structural features are important. Emphasis will be placed on the role of the carbohydrates. 1. Calicheamicin: Calicheamicin is an ene-diyne antitumor antibiotic that binds to and cleaves DNA. The oligosaccharide tail of calicheamicin is the principal DNA binding element. In order to learn more about how the calicheamicin oligosaccharide recognizes DNA, analogues will be synthesized and their binding properties evaluated. The design of the analogues will be based on a series of NMR structures which have led to a hypothesis for how binding selectivity is achieved. II. Chromomycin A3: Chromomycin A3 (CRA3) is an aureolic acid antitumor antibiotic that forms a diastereoisomeric 2:1 complex with Mg2+. This dimeric complex binds to DNA and inhibits DNA and RNA polymerases. The trisaccharide side chain of CRA3 plays a key role in organizing the diasteroisomeric Mg2+ complex. In order to learn more about the structural requirements for dimer formation and DNA binding, analogues will be synthesized and evaluated. The ability to control the shape of metal complexes using non-covalent interactions could have applications well beyond the design of new DNA binders with potential antitumor activity. III. Aclacinomycin: Aclacinomycin is an anthracycline antitumor antibiotic that binds to DNA It also inhibits topoisomerase activity. The trisaccharide plays a critical role in topoisomerase inhibition. Experiments to elucidate the mechanism of topoisomerase inhibition are proposed.
| Specht, K M; Nam, J; Ho, D M et al. (2001) Determining absolute configuration in flexible molecules: a case study. J Am Chem Soc 123:8961-6 |
