Research Interests

• The Ellis Group conducts research at the interface of medicinal chemistry, organic synthesis, and chemical biology that investigates natural products with novel or unknown mechanisms of action. As part of these projects we use organic synthesis to prepare natural products and analogs by both semi-synthesis from naturally obtained material and by total synthesis. We then use these molecules as chemical probes to examine the biological activity, identify the molecular target, and elucidate the mechanism of action of the natural product. Once the molecular target and mechanism are known, we evaluate the SAR, prepare more potent analogs, develop new assays, screen chemical libraries for other scaffolds that interact with the new molecular target, and begin to evaluate the pharmacokinetics and pharmacodynamics.
• Projects:
• Simocyclinone D8: A Novel Topoisomerase II (TopoII) inhibitor – Simocyclinone D8 is an angucyclinone natural product that has been reported to inhibit type-II topoisomerases, which include DNA gyrase (a validated anti-bacterial drug target) and human TopoII (a validated anti-cancer drug target). We have obtained simocyclinone D8 by fermentation, extraction, and purification from the S. antibioticus Tu 6040 bacteria. We are currently developing a relay synthesis of the natural product and preparing analogs by semi-synthesis, which will be tested against the type-II topoisomerase enzymes.
• Grifolin: An Apoptosis-Inducing Agent – Grifolin is a farnesylated natural product isolated from several mushroom species that has been reported to induce apoptosis in cancer tumor cells in vitro. Induction of apoptosis in tumor cells treated with grifolin was accompanied by increased levels of Bax expression, decreased levels of Bcl-2 expression, release of cytochrome c, and increased levels of caspases-8, -9, and -3. Grifolin-induced apoptosis was also accompanied by a reduction in the level of phosphorylated Akt, demonstrating that inhibition of the Akt signal cascade occurred upstream of Akt itself. This project is using the natural product grifolin as a chemical probe to determine the molecular target and mechanism by which it induces apoptosis. Our hypothesis is that grifolin induces apoptosis by inhibiting farnesyltransferase (FTase). We speculate that grifolin’s farnesyl chain competitively binds in the farnesyl pyrophosphate binding site on FTase and inhibits transfer of the farnesyl moiety to K-Ras, thereby preventing activation of the PI3K/Akt pathway. FTase inhibitors (FTIs) have been shown to inhibit the PI3K/Akt signal cascade and induce apoptosis. We are currently in the process of synthesizing grifolin and analogs.
• Along with our projects, we are collaborating with other groups to develop small molecule modulators of biological activity and to develop new technologies for drug development and delivery:
• Collaborative Projects:
• Inhibitors of ErmC/KsgA (Jason Rife, VCU SOM)
• Minosaminomycin as a targeted tuberculosis inhibitor (Jason Rife, VCU SOM; John Hackett, VCU Med Chem)
• Microwave Microfluidics Reactors for the Synthesis of Advanced Pharmaceutical Ingredients (Frank Gupton, VCU Chemical & Life Sciences Engineering)