Small molecules capable of protecting cells from death have the potential to be excellent pharmaceuticals in the context of many disease states, including heart attack, stroke, traumatic brain injury, and neurodegeneration. Unfortunately, for many reasons cytoprotective compounds able to significantly alter the progression or prognosis of any of these disease states have yet to be discovered. Thus identifying new cytoprotective compounds or new cellular pathways to target for cytoprotection could lead to both enhancements in understanding the underlying biology and improvements in the quality of patient's lives.
Dykellic acid, a small molecule isolated from the fermentation broth of the soil fungus Westerdykella multispora, was identified as possessing cytoprotective properties against camptothecin-induced cell death. Described herein is the first total synthesis of dykellic acid, completed in eight linear steps. The synthesis of several dykellic acid derivatives is also described. The cytoprotective ability of dykellic acid was assessed against four toxins, etoposide (a topoisomerase II inhibitor used as a model for cellular damage due to chemotherapeutics), rotenone (a mitochondrial complex I inhibitor used as a model of Parkinson's disease), N-methyl- N'-nitro-N-nitrosoguanidine (MNNG) (a DNA alkylating agent), and hydrogen peroxide (a reactive oxygen species (ROS) used as a model for oxidative damage). Of these toxins, dykellic acid was able to strongly protect cells from etoposide- and rotenone-induced cell death. It was also found to be protective against MNNG, but to a lesser extent. Analysis of the synthetic derivatives of dykellic acid established key functional groups of the molecule that are essential for its cytoprotective activity.
Experiments were also carried out to establish if dykellic acid's biological activity can be attributed to either of two well-established mechanisms, ROS quenching or caspase inhibition. Using fluorescent dyes sensitive to ROS it was established that dykellic acid is not capable of directly quenching ROS. Dykellic acid was also found to not directly inhibit caspase enzymes, an important family of enzymes in cellular death. While the mechanism of action of dykellic acid has yet to be elucidated, dykellic acid's potency and apparently nonstandard mechanism of action make it an interesting candidate for evaluation in models of cytoprotection.
|Advisor:||Hergenrother, Paul J.|
|School:||University of Illinois at Urbana-Champaign|
|School Location:||United States -- Illinois|
|Source:||DAI-B 70/02, Dissertation Abstracts International|
|Keywords:||Cytoprotective, Dykellic acid, Westerdykella multispora|
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