|
Tobacco is responsible for 30% of all cancers, and 1 in 5 deaths in the U.S. every year. Tobacco use places individuals at increased risk for lung, mouth, pharynx, larynx, esophagus, pancreas, cervix, kidney, and bladder cancers as well as heart disease and a range of other conditions. Because tobacco is responsible for such a wide variety of afflictions, there are many different approaches which could be able to reduce the negative impact of tobacco related diseases. Synthetic organic chemistry is uniquely suited to the production of new drug candidates for screening for activity against these diseases.
At least two thirds of all drugs approved for the treatment of cancer are either natural products or natural product derivatives. Every year new compounds with promising biological activity are found; however, without sufficient material, promising new drug candidates cannot be studied to determine their full potential. Additionally, while some compounds may display only moderate activity, analogs of those compounds, created by making small changes to the basic chemical structure, may exhibit much greater activity and/or selectivity. A more active drug will require a smaller dose to be effective, while a more selective drug will produce fewer side-effects. Because many current drugs require large doses or produce undesirable side-effects, the development of new drug candidates is a very important and ongoing area of research. Unfortunately, most of these promising new compounds are not readily available from their natural sources in large quantities, and most analogs are only available by synthesis. The development of efficient synthetic routes to promising biologically active compounds is critical for the discovery and development of drug candidates that are necessary in the ongoing battle against cancer and other diseases.
A new group of compounds, the glaciapyrroles, has been disclosed recently that exhibit promising anticancer activity that has not been fully studied due to the small amounts of the material available from the natural source. Additionally, these molecules possess a chemical structure that is difficult to produce selectively. The structure and the small size of these molecules make them ideal candidates for analog studies. Described in this proposal is a new method of our invention that is uniquely effective at generating this key challenging chemical structure, and a plan to synthesize these promising new anticancer compounds and analogs. These compounds will be screened for their ability to inhibit the growth of different types of cancer represented by the National Institute of Health’s 60 cancer cell lines. Many current anticancer drugs are large, complex molecules that require lengthy synthetic routes that are often not adaptable towards the creation of analogs. Our proposed routes towards these three small molecules all require 10 or less linear steps; because the two halves of the molecules are created separately, these routes can easily accommodate small changes to the basic chemical structure needed to produce analogs. Because these routes are very short compared to the syntheses of many organic compounds and currently available drugs, a large number of analogs will be created and screened very quickly. Efficient synthesis and quick screening will enable the swift discovery of promising new drug candidates. |
