Newly discovered methyl tortuoate A and methyl tortuoate B were recently isolated from Sarcophyton tortuosum along with known methyl sartortuoate. Possessing two unique tetracyclic frameworks, methyl tortuoate A and B exhibit potent in vitro cytotoxicity against the human nasopharyngeal carcinoma CNE-2 cell line and the murine P-388 tumor cell line. The ability to design and modify a proposed synthesis to access these potential drugs and numerous analogs could provide another anticancer drug. In addition, the isolation of these natural products proved arduous with 300 grams of dried soft coral providing around 10 mg of each compound. As a result, very little is currently known about their mechanism of action. In this proposal, a reliable, highly convergent and adaptable synthesis for methyl tortuoate A will be addressed that, if successful, will provide sufficient quantities to examine the structure-activity relationships (SARs) and possibly reveal a more potent anticancer drug. The syntheses of these tetracyclic molecules rely on constructing the same A-ring dienophile and performing a Diels-Aldler reaction to produce the B-ring. Since the differences in these molecules come in the C,D-ring segments, these segments will be constructed in two different paths. For methyl tortuoate A, a modified Julia-coupling and transannular epoxide-opening macrocyclization will be employed, while methyl tortuoate B relies on a modified-Julia coupling, a Nozaki-Hiyama-Kishi (NHK) closure, and a novel tetrahydrofuran ring cyclization. Newly discovered methyl tortuoate A and methyl tortuoate B exhibit potent in vitro cytotoxicity against the human nasopharyngeal carcinoma CNE-2 cell line and the murine P-388 tumor cell line. The total syntheses of these molecules have been proposed and, if successful, would provide sufficient quantities to gain a better understanding of their mechanisms of action within cells. ? ? ?
| Peyrot des Gachons, Catherine; Uchida, Kunitoshi; Bryant, Bruce et al. (2011) Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci 31:999-1009 |
