| Description |
Bryostatin 1 is a complex macrolactone natural product isolated from the marine bryozoan Bugula neritina. In recent years, bryostatin 1 has been studied in diseases like cancer, Alzheimer's, stroke, and HIV. The anticancer activity of bryostatin 1 has led to many phase I and phase II clinical trials, and its ability to block the formation of plaques has led to phase II clinical trials for Alzheimer's disease. Bryostatin 1 has been found to be a functional antagonist for protein kinase C mediated responses, and does not exhibit tumor-promoting properties that are associated with phorbol esters. There is a necessity to produce additional amounts of the marine natural product bryostatin 1 because of it incredibly rich biological profile. One way to address supply issues is through chemical synthesis of bryostatin 1. The first total synthesis of bryostatin 1 was accomplished in 30 longest linear steps and a total of 55 steps. This synthesis involved a highly convergent union of the A-ring and C-ring using the pyran annulation methodology developed by our group. The synthesis of bryostatin 1's C-ring features a olefin/carbonyl metathesis reaction leading to a method to produce fully functionalized C-ring. Bryostatin 7 was also constructed using our synthetic route, and its biological profile was evaluated. Bryostatin 7 differs from bryostatin 1 at the C20 side chain and was found to not be a critical element of bryostatin 1 to obtain the biological responses typical of bryostatin 1. Constructing simplified bryostatin analogs is another method to address the supply issues of bryostatin 1. Our group has prepared structurally simplified analogs of bryostatin that rivaled or exceed the activity of bryostatin 1 itself. In 2008, we constructed a structurally simplified bryostatin analog Merle 23 that displayed "PMA-like" activity in the U937 cell line. We later constructed Merle 28, an analog that resembles bryostatin 1 closely, that displayed "bryo-like" activity in the U937 cell line. With these results, we hypothesized that the northern half of bryostatin is not simply a spacer domain as suggested in the literature. In order to understand the underlying mechanism of action of Merle 23 and Merle 28, the design and synthesis of fluorescent analogs were accomplished using a fully functionalized C-ring in our pyran annulation reaction. Incorporation of a fluorescent tag at the C20 position did not have substantial effects on the biological profile (binding affinity for PKC, U937 cells, and Toledo cells). Merle 44 (fluorescent Merle 23) was found to be a functional analog of Merle 23 and Merle 45 (fluorescent Merle 28) was found to be a functional analog of Merle 28. |
