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Syntheis of the anti-cancer norcembranoid inelegnolide

Institution: University of California, Irvine
Investigator(s): Evan Horn, B.S.
Award Cycle: 2010 (Cycle 19) Grant #: 19DT-0008 Award: $59,388
Subject Area: Cancer
Award Type: Dissertation Awards
Abstracts

Initial Award Abstract
In 1964, the Surgeon General of the United States reported a correlation between smoking cigarettes and the incidence of lung cancer. This report stated that the risk for developing lung cancer increased proportionally to the amount smoked, and that smokers were at a ten times higher risk for lung cancer compared to non smokers. Since this report, smoking has been directly linked to a number of other cancers, including pancreatic, kidney, bladder and prostate cancer and leukemia. This direct correlation between cancer incidence and smoking, coupled with the high mortality rate for many of these diseases, has stimulated the continual development of new anticancer pharmaceuticals. Natural products serve as a important tools to combat these smoking-related cancers. As of 2002, 74% of all anticancer pharmaceuticals in use were either natural products, or natural product derivatives. Synthetic organic chemistry plays an invaluable role in the development of these new drug candidates. Each year many new bioactive natural products are discovered; however, these potential pharmaceutical agents are often isolated in such small quantities that full biological assessment is not possible. Furthermore, analogs of these natural products may exhibit greater biological potency or selectivity than the natural products themselves. The development of an efficient synthetic route to a biologically active natural product can provide sufficient quantities of a compound to allow further biological studies and allows the generation of unnatural analogs available only by synthesis, which may be developed into pharmaceutical agents. The cembranoids (and the closely related norcembranoids) are a large class of natural products that have been isolated from a number of marine invertebrates. Many of these compounds have shown significant potency against various cancer cell lines. The norcembranoid natural product ineleganolide was isolated in 1999 from a soft coral, and has displayed activity against human leukemia cells; however, the minute amount of sample collected prohibited further testing. In addition to its potential biological activity, ineleganolide is also related to a number of other bioactive natural products by a series of relatively simple biosynthetic disconnections. It may be possible to convert ineleganolide into other known and unknown norcembranoid compounds, which will likely display anti-cancer activity. The objective of this application is to complete a concise enantioselective synthesis of ineleganolide from commercially available starting materials. Our proposed synthesis, consisting of approximately a dozen steps, should allow us to supply substantial amounts of ineleganolide for further screening against a range of cancer cell lines, as well as investigate the possibility of using ineleganolide as a precursor to other natural and unnatural biologically active norcembranoids.