Jeffrey D. Winkler

New Synthetic Pathways Based on the Intramolecular Dioxenone and Vinylogous Amide Photocycloaddition Reactions

We have developed these methods and have applied them to the first total syntheses of several molecules of biological importance, including manzamine A, 1, saudin, 2 , and ingenol, 3.

Total Synthesis of Manzamine-Related Structures

Current efforts in our laboratory are focused toward the synthesis of nakadomarin, 4, a structurally complex hexacyclic alkaloid that displays a range of promising biological activities including cytotoxic activity against murine lymphoma L1210 cells, inhibitory activity against cyclin dependent kinase 4, and anti-microbial activity against a fungus and a Gram-positive bacterium. We have also demonstrated that manipulation of the structure of 1 via Grubbs metathesis leads to the formation of novel structures, i.e., 5, with antibacterial properties comparable to those of ciprofloxacin. Finally, we have embarked on a program directed toward the synthesis of neokauluamine, 6, a dimeric manzamine with highly potent immunosuppressive properties. 

Transformations Using Organic Photochemistry

We have recently discovered a novel approach to the synthesis of substituted thiophenes 8 from arylsulfide enone precursors 7. The study of the mechanism of this unusual transformation (9 is a byproduct) as well as its application to the synthesis of more complex structures is currently underway in our laboratory.

Development of Novel Inhibitors of Hedgehog Signaling Based on Cyclopamine

Aberrant activation of the Sonic Hedgehog (Hh) signaling pathway has been associated with numerous malignancies in the brain, breast, pancreas and other organs. In vivo evidence suggests the antagonism of excessive Hh signaling may provide a route to unique mechanism-based therapies for the treatment of cancer. The steroidal alkaloid cyclopamine 10 suppresses the Hh signaling pathway, and has recently been been shown to be effective in the treatment of cancer using a variety of mouse models. Human cells are also sensitive, supporting the promising use of this natural product. However, the metabolic instability of cyclopamine precludes its clinical use. A significant demand exists for more stable cyclopamine-like structures. This project is directed toward the synthesis of cyclopamine-like structures, i.e., 11, from readily available metabolically-stable steroidal precursors, i.e., estrone.

Total Synthesis of Cortistatin A

The development of specific anti-angiogenic agents that could serve as anticancer chemotherapeutic agents is an important goal. In 2006, Kobayashi isolated the cortistatins from the marine sponge Corticium simplex. Cortistatin A 12 is the most active member of this family. It exhibits antiproliferative activity against human umbilical vein endothelial cells at nM concentrations. The total synthesis of the cortistatins and designed materials with cortistatin-like properties is one of the goals of our laboratory.