Total synthesis and cytoprotective properties of dykellic acid.

Small molecule inhibitors of apoptosis hold considerable promise for the treatment of a host of diseases, including neurodegeneration, myocardial infarction, and stroke. Many compounds that delay or prevent apoptotic death either reduce the amount of cellular reactive oxygen species (ROS) or are direct inhibitors of caspases. With the goal of using small molecules to identify novel antiapoptotic targets, we have investigated the cytoprotective activity of the natural product dykellic acid. Described herein is the first total synthesis of dykellic acid, the synthesis of several dykellic acid derivatives, and the evaluation of these compounds in assays related to cell death. We have found that dykellic acid protects cells from death as induced by etoposide and rotenone. Further experiments strongly suggest that dykellic acid does not scavenge ROS or directly inhibit caspase enzymes, and analysis of synthetic derivatives establishes key functional groups of the molecule that are essential for its cytoprotective activity.