Total Synthesis of Anticancer Compounds: The Neomangicols
Abstracts
Initial Award Abstract |
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Lung cancer is one of the most fatal diagnoses a patient can receive. Within five years of diagnosis, 83% of lung cancer patients die. Lung cancer accounted for around 28% of the greater than half-a-million cancer deaths in the United States in 2004, which amounts to over 160,000 people dying because of this disease. Smoking tobacco products is the principal lifestyle factor that contributes to the onset of lung cancer. The combined ineffectiveness of current treatments and the addictive nature of cigarettes and other nicotine containing products means that new drugs are needed to treat the cases of lung cancer that will continue to proliferate into the future. The search for effective cancer drugs is a daunting task. It involves finding a compound that not only works to kill the targeted cancer cells, but also making sure that this compound will not target other healthy, normal cells. In addition, the compound must be easily administered and available in the bloodstream to have a positive effect on a patient. One method of finding such a compound is to test hundreds of thousands to millions of chemicals to find one that will kill the cancer cells, but after this, the other hurdles must still be overcome. Products isolated from nature have a head start on these "libraries" of chemicals used in the previous method. So-called natural products have been used in herbal and homeopathic remedies for ages. These compounds can be isolated from natural source and administered in a more concentrated form, such as penicillin and aspirin. These natural products have been evolved over thousands to millions of years to interact with biological systems selectively. They also often have properties that make them compatible in biological systems. These characteristics make natural products promising compounds for drugs. There are already instances of using natural products for the treatment of cancer. The drug Taxol is a natural product isolated from the pacific yew tree. This drug has shown remarkable use in the treatment of breast cancer. Unfortunately, the relatively low levels of the drug required the cutting down of six 100-year old trees for the treatment of a single patient. The drug is now produced through a combination of bacterial production of an advanced intermediate, followed by organic synthesis to carry the material through the last few steps to yield the product. Unfortunately, the natural products themselves are often not perfect, even though they offer a significant head-start. In this case, compounds with much the same structure are made to see if slight changes can tweak the activity and selectivity. This offers the chemist and biologists opportunities to make specific changes, and to learn about the system in hand. This process can be most easily be done by total synthesis, or the synthesis of compounds from petroleum derived products. This work will deal with the total synthesis of a number of anti-cancer natural products, the neomangicols. The neomangicols are a class of sesteterpenes isolated from a marine fungus in the Fusarium genus in the Bahamas. Neomangicols A and B were both found to be active against MCF-7 (human breast carcinoma) and CACO-2 (human colon carcinoma). There is evidence of cross-sensitivity for non-small cell lung carcinoma and human colon carcinoma. The compounds exhibit a unique tetracyclic core not found in any other natural products to date. The unique structure of these compounds gives hope of a novel mode of action that can be explored for their activity. The neomangicols were isolated in extremely low quantities from a fungal extract (less than 10 mg per liter of extract combined). Because of this low abundance from the natural source, a total synthesis of the neomangicols is required to obtain enough material for adequate biological investigation. This will allow the neomangicols to be screened against a wider array of cancer cell lines, including the tobacco related disease cell lines like non-small cell lung carcinoma and acute myelocytic leukemia. |
Publications
| Systhesis of the tetracyckic core of the neomangicols using a late-stage indene alkylation. |
| Periodical: Org. Lett |
Index Medicus: |
| Authors: Wood, JL; Punjanauski, BG; Sarpong, R |
ART |
| Yr: 2009 |
Vol: 11 |
Nbr: |
Abs: |
Pg: 3128-3131 |
| Systhesis of the tetracyckic core of the neomangicols using a late-stage indene alkylation. |
| Periodical: Org. Lett |
Index Medicus: |
| Authors: Wood, JL; Punjanauski, BG; Sarpong, R |
ART |
| Yr: 2009 |
Vol: 11 |
Nbr: |
Abs: |
Pg: 3128-3131 |
