The thereapeutic importance of antitumor and antiviral agents requires a continued effort to develop new methodology to define significantly improved efficient synthetic strategies to better understand structure - biological activity relationships. Choosing classes of compounds known for this type of biological acitivity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Four general types of chemical reactions under investigation to improve selectivity and atom economy serve as the new core technology to realize these goals - asymmetric allylic alkylation, cycloadditions to form odd membered rings, unprecedented C-C bond forming reactions by simple additions, and the ability to spontaneously self-assemble dinuclear metal complexes for asymmetric catalysis. Indoline alkaloids represented by rather diverse structures such as communesins, gliocladins/leptosins, and diazonamides as well as iboga type alkaloids represented by vindoline and kopimaline A are greatly simplified by examining new classes of nucleophiles for palladium and molybdenum catalyzed asymmetric allylic alkylation. Examination of the prospect of an unprecedented [6+3] asymmetric cycloaddition provides access to a novel oxindole alkaloid that addresses multidrug resistance. Macrocyclic lactones constitute a highly diverse array of structural types possessing potent and diverse activities as anti-cancer and antiviral agents. The very potent laulimalide and the amphidinolides, whose structures need confirmation, represent structural types that probe new directions for ruthenium catalyzed C-C bond formation. Peluroside A, a highly active inducer of apoptosis, and the salicylate macrolactones represented by apicularin A stimulate multiple new applications of asymmetric catalysis using dinuclear metal complexes. The densely functionalized pholactomycins which show diverse activity represented by leustroducsin B, a potent cytokine inducer, may simplify to a highly convergent strategy where its stereochemistry largely derives from both the dinuclear metal complexes and the asymmetric allylic alkylation reaction.
Inventing new drugs for the treatment of cancer and viruses requires a better understanding of mechanisms and the relation of structure to function. This proposal helps to address this key challenge by developing the underlying initial technology within classes of compounds having demonstrably antitumor or antiviral activities.
Showing the most recent 10 out of 123 publications
