Sclerophytin A is a complex naturally occurring compound that exhibits potent anticancer activity in vitro. We are in the process of synthesizing sclerophytin A so as to make larger quantities available for biological assays. We have thus far prepared an advanced intermediate that possesses 6 of the 8 stereocenters and 18 of the 20 carbons of the natural product. We propose to complete the synthesis in an additional 7 steps from the advanced intermediate. Massileunicellin B is a natural product from the same family as sclerophytin A, but is more stereochemically complex, possessing 9 contiguous stereocenters. We have prepared an advanced intermediate that possesses 8 of the 9 stereocenters and 19 of 20 of the skeletal carbons. We propose to complete the synthesis by a modification of the original route that will entail an additional 8 steps from an advanced intermediate analogous to one prepared in the original route. Using the chemistry developed for the total syntheses, we have prepared simplified analogs of sclerophytin A that are available in as few as 3 chemical steps. Preliminary growth inhibition assays suggest that these simple analogs may prove to be promising anticancer agents. One such analog exhibits an IC50 against KB3 cells of 20 mM in an MTT assay. A pilot scale library will be prepared and assayed to probe for structural features that will result in analogs with increased potency. A key step in the sclerophytin A synthesis involves a novel SN2' reaction of an ?-alkoxymethyl Cu nucleophile. We propose to further explore the scope of this reaction with a variety of allylic esters and related electrophiles. The goal of the projects described in this proposal involves the laboratory synthesis of promising anticancer agents. The successful development of these agents could result in improved anticancer chemotherapies. ? ? ?
| Chai, Yonghai; Mou, Zonghong; McIntosh, Matthias C (2010) Studies directed toward the synthesis of the massileunicellins. 2. Tetrahedron Lett 45:3269-3272 |
| Bateman, T David; Joshi, Aarti L; Moon, Kwangyul et al. (2009) Synthesis and anticancer activity of sclerophytin-inspired hydroisobenzofurans. Bioorg Med Chem Lett 19:6898-901 |
