Preparation of icetexane diterpenoids: synthesis of breast cancer cell growth inhibitors
| Author(s) | Moon, Daniel | |
| Date Accessioned | 2017-03-23T12:05:26Z | |
| Date Available | 2017-03-23T12:05:26Z | |
| Publication Date | 2016 | |
| Abstract | Breast cancer is one of the most common cancers among women worldwide. Late stage treatment for breast cancer involves a chemotherapeutic, doxorubicin, which has earned the nickname “the red death” due to the detrimental side effects associated with this drug. Therefore, it is urgent that we identify and study recently discovered breast cancer drugs capable of treating cancer patients. Premnalatifolin A, an icetexane diterpene dimer, was recently isolated and evaluated against multiple cancer cell lines, in particular MCF-7 breast cancer cells (IC50 = 1.77 μM), outperforming doxorubicin (IC50 = 3.68 μM). The monomeric unit was also found to be selectively cytotoxic against MCF-7 cell line (IC50 = 3.53 μM). ☐ Given that both the dimer and monomer exhibited anti-cancer activity, our goal was to develop synthetic pathways for the tricyclic backbone of the monomer. We have developed two synthesis pathways to forming the 3-vinyl siloxybenzyl halide and a one-step synthesis of both the unsubstituted and 4,4-dimethyl-substituted vinylated silyl enol ether, and during the course of our work we developed optimized conditions for the Suzuki-Miyaura coupling of an aryl chloride. We attempted utilizing the enolate–ortho-quinone methide Michael addition, a reaction sequence notable in our group, to join the two cyclic fragments. Due to complications resulting from an unproductive hemiacetal formation, we revised the synthesis by diverting to a classic alkylation reaction sequence. The classical enolate alkylation was highly diastereoselective, giving the desired 1,2-trans alkylation product, which was followed by a ring-closing metathesis reaction to construct the 7-membered ring and complete the core structure of these important natural products. Furthermore, we explored the hydrogenation of the cycloheptene ring, opening up the synthesis to generate a small library of icetexane model compounds. | en_US |
| Advisor | Chain, William | |
| Degree | M.S. | |
| Department | University of Delaware, Department of Chemistry and Biochemistry | |
| Unique Identifier | 978290812 | |
| URL | http://udspace.udel.edu/handle/19716/21158 | |
| Publisher | University of Delaware | en_US |
| URI | https://search.proquest.com/docview/1840893189?accountid=10457 | |
| Title | Preparation of icetexane diterpenoids: synthesis of breast cancer cell growth inhibitors | en_US |
| Type | Thesis | en_US |