Application Epoxides, Leukotrienes, and Asthma

The opening of epoxide rings with nucleophiles is a key step in some important biological processes. 

Leukotrienes were first synthesized in 1980 in the laboratory of Professor E. J. Corey, the 1990 recipient of the Nobel Prize in Chemistry. 

The leukotrienes are molecules that contribute to the asthmatic response. A typical example, leukotriene C4, is shown. Although its biological activity was first observed in the 1930s. the chemical structure of leukotriene C4 was not determined until 1979. Structure determination and chemical synthesis were difficult because leukotrienes are highly unstable and extremely potent, and are therefore present in tissues in exceedingly small amounts. 

Leukotrienes are synthesized in cells by the oxidation of arachidonic acid to 5-HPETE, which is then converted to an epoxide, leukotriene A4. Opening of the epoxide ring with a sulfur nucleophile RSH yields leukotriene C4. 

New asthma drugs act by blocking the synthesis of leukotriene C4 from arachidonic acid. For example, zileuton (trade name Zyflo) inhibits the enzyme (called a lipoxygenase) needed for the first step of this process. By blocking the synthesis of leukotriene C4, a compound responsible for the disease, zileuton treats the cause of asthma, not just its symptoms. 

Generic name albuterol Trade names Proventil. Ventolin 

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