Inspiration from Triptolide: new synthetic methods and probes

Abstract

Chinese medicinal plant, Tripterygium wilfordii Hook F (‘Thunder God Vine’ or Lei Gong Teng), is a vine-like herb used for centuries to combat the symptoms of rheumatoid arthritis, systemic lupus erythematosus and psoriasis. Triptolide, a diterpenoid with a triepoxide structure, is the most active compound isolated from this herb and exhibits extremely potent anti-tumor, anti-inflammatory, and immunosuppressive activities. Inspired by triptolide’s complex structure, we have developed ketone-catalyzed oxidation re¬actions (epoxidation, C–H bond oxidation, and heteroatom oxidation) and asymmetric cyclization reactions. By developing efficient and enantioselective syntheses of triptolide analogs and probes, we have identified structural features important for the biological activities of triptolide. We have also identified several cellular targets of triptolide, which will lead to a better understanding of cell growth regulation and immune responses, as well as discovery of new anticancer, anti-inflammatory, and immunosuppressive drugs. We have also successfully applied new oxidation chemistry to the development of highly specific and sensitive fluorescent probes for the cellular imaging of peroxynitrite, a potent oxidant involved in many human inflammatory diseases. These probes are useful tools to study the mecha¬nisms of human diseases and the aging processes related to the production of reactive oxygen species.