Photochemical Key Steps in Cyclization Reactions: Synthesis of Isoindolone Piperidines As Kinase Inhibitors
Tynai J. Bridges1, Hayley T. Allen2, Matthew G. Donahue2, Wolfgang H. Kramer*1
1Department of Chemistry and Biochemistry, Millsaps College, Jackson, MS
2Department of Chemistry and Biochemistry, The University of Southern Mississippi, Hattiesburg, MS
Cancer cell are the result of disruption of tightly regulated metabolic pathways. This leads to uncontrolled proliferation of cells as seen in invasive tumors. Inhibition of certain metabolic enzymes thus might provide a tool to minimize the harmful effects of excessive cell growth. Two key phosphorylating enzymes, glycogen synthase kinase-3 (GSK3) and cyclin-dependent kinases (CDKs) are the target of researchers to interfere with cancer metabolism. Valmerins are isoindolone piperidines that have been shown to inhibit GSK3/CDK enzymes during cell proliferation. In this project, we are using the photodecarboxylative cyclization as a key step in the synthesis of GSK3/CDK inhibitors. The syntheses are initiated from affordable building blocks and culminate in the stereocontrolled synthesis of the target molecules.
Acknowledgement: This work was supported by the Mississippi INBRE, funded by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103476.