Porco Group Awarded $1.6 million to Investigate Biomimetic Synthesis of Complex Natural Products

John Porco
Professor John Porco

Professor John Porco and his group have received a 4-year, $1.6 million award (2010 to 2014) to develop and refine biomimetic syntheses using copper-mediated enantioselective oxidation processes; photochemical cycloaddition employing excited state intramolecular proton transfer (ESIPT); and asymmetric reactions of acylphloroglucinols. Professor Porco and colleagues are applying these methodologies to synthesize complex natural products, including bisorbicillinol, sorbicillactone A, aglaiastatin, ponapensin, and myrtucommulones A and B. Collaborating with the Porco Group is Prof. Linda Doerrer who is performing mechanistic investigations to understand copper-mediated enantioselective oxygenase and oxidase processes and also develops catalytic, asymmetric oxidation processes. Likewise, a continuing collaboration with Professor Eric N. Jacobsen and coworkers (Harvard University) seeks to identify chiral thiourea photocatalysts for asymmetric photocycloadditions. Collaborations are also in place with biological collaborators including Dr. John A. Beutler (Molecular Targets Development Program, National Cancer Institute) and Professor Jerry Pelletier (McGill University) to evaluate compounds as anticancer agents and protein translation inhibitors. This work aims to identify novel, bioactive molecules that are potentially novel pharmacological tools and cytotoxic agents for treatment of various prevalent human malignancies, including human cancers. For example, the Pelletier Group found that the rocaglate natural product silvestrol synthesized by the Porco Group could reverse chemoresistance in tumors containing lesions in the PI3Kinase/Akt pathway or overexpressing eIF4E. In addition, they determined that silvestrol exhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increased apoptosis, decreased proliferation, and inhibition of angiogenesis (“Antitumor activity and mechanism of action of the cyclpenta[b]benzofuran, silvestol” Cencic, R., Carrier, M., Galicia- Vazquez, G., Bordeleau, M.E., Sukarieh, R., Bourdeau, A., Brem, B., Teodore, J.G., Gerger, H., Tremblay, M.L., Porco, J.A Jr., Pelletier, J. PloS ONE 2009 4(4):e5223.) It appears that silvestrol targets translation initiation to cause preferential inhibition of weakly initiating mRNAs. The Porco Laboratory has recently identifiedrocaglate analogues that are approaching the potency of silvestrol as a protein translation inhibitor. To date, this work has resulted in 12 publications and 2 patents.