Parallel Synthesis and Biocatalytic Amplification of Marine-Inspired Libraries: An Integrated Approach Toward Discovering New Chemotherapeutics

摘要

We have made further progress toward preparing lead compounds for new anticancer drugs from a novel class of starting materials containing the cyclopentenone scaffold. Two diastereomeric natural-product IL-6 inhibitors, madindolines A or B, were also prepared via an exceptionally efficient synthesis. The new cyclopentenones comprise a library of complex, polyfunctional organic molecules of unprecedented structure. The most important class of enzymes for biocatalytic amplification of these compounds is the cytochrome P450s. We have developed and optimized new reaction systems (e.g., surfactantstabilized two-phase emulsions) that will expand the synthetic utility of cytochrome P450s and render them much more effective catalysts for structural elaboration of the chemically synthesized compounds. We also used a novel 3D cell-culture chip to screen cyclopentenone libraries for inhibitory activity toward cytochrome P450s and for cytotoxicity against cancerous breast cells. The toxicities of select cyclopentenones were investigated further by screening against both cancerous and normal breast cells. These screens revealed structural differences in the cyclopentenones responsible for variations in their toxicity toward cancerous cells, and for greater toxicity toward normal versus cancerous cells. Combining combinatorial synthesis with biocatalytic amplification of chemical libraries is a new approach to drug discovery, which we are applying to a promising but largely unexplored class of compounds.