Total synthesis of cribrostatin 4, a potent anticancer agent
Abstracts
Initial Award Abstract |
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Lung cancer is now the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. More than 80% of lung cancer is caused by cigarette smoking and compared with nonsmokers, smokers have a 10-fold greater risk of dying from lung cancer, and in heavy smokers this risk increases to 15- to 25-fold. Two major types of lung cancer associated with smoking are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter accounting for 75 to 80% of all lung cancer cases. Since both tumors are uniformly aggressive and the majority of them are unresectable, the poor survival statistics reported to date (~14% with a 5 year survival rate) indicates that the currently available therapies are only of limited efficacy. One major responsible factor is that the cancer is detected at a stage when it has already spread to other parts of the body by metastasis (spread of cancer through blood or lymphatic systems). Owing to the severity of these diseases and the dark prognosis for many patients suffering from these types of cancer, there is an urgency for the development of new effective anticancer drugs that would target lung cancer and a whole variety of cancer cells as a result of metastasis.
The influence of natural products upon anticancer drug discovery and design cannot be overstated. Approximately 65% of all approved drugs for the treatment of cancers are either natural products or natural product derivatives. Cribrostatin 4 is a complex natural product isolated from the blue marine sponge Cribrochalina species in reef passages in the Republic of Maldives. This compound displays potent anticancer properties against a wide variety of human cancer cell lines including NSCLC. An obstacle encountered with this natural product is that the amount available from its natural source is limited, and massive collection of the marine sponge is costly and ecologically unacceptable. Segments of the Cribrostatin 4 core structure are related to the more complex Ecteinascidin 743, a potent anticancer agent (~50 fold more potent than the anticancer drug Taxol), currently undergoing phase II clinical trials for cancer therapy. The possibility that a relationship may exist in the mechanisms of action of the two natural products remains unproven. Because of its limited availability, no further studies were conducted to investigate its mechanism of action and its potential use as an anticancer drug. Chemical synthesis is the only viable means to access ample quantities necessary for advanced studies. Since Cribrostatin 4 has not been synthesized previously, we propose to chemically synthesize this compound with a view to deliver meaningful quantities for advanced studies. With a synthetic pathway established, we also plan to synthesize a variety of Cribrostatin 4 analogs that will be tested for anticancer properties against human lung cancer cells and other cancer cell lines at the National Cancer Institute. We hope that the results from this study will generate drug candidates for the treatment of lung cancer and other related metastatic cancers. |
Publications
| Palladium-catalyzed oxidative wacker cyclizations in nonpolar organic solvents with molecular oxygen: a stepping stone to asymmetric aerobic cyclizations. |
| Periodical: Angewandte Chemie (International Ed. in English) |
Index Medicus: |
| Authors: Trend RM, Ramtohul YK, Ferreira EM, Stoltz BM |
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| Yr: 0 |
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| Palladium-catalyzed oxidative wacker cyclizations in nonpolar organic solvents with molecular oxygen: a stepping stone to asymmetric aerobic cyclizations. |
| Periodical: Angewandte Chemie (International Ed. in English) |
Index Medicus: |
| Authors: Trend RM, Ramtohul YK, Ferreira EM, Stoltz BM |
ART |
| Yr: 0 |
Vol: |
Nbr: |
Abs: |
Pg: |
