Synthesisof seco-B-Ring BryostatinAnalogue WN-1 via C–C Bond-Forming Hydrogenation: CriticalContribution of the B-Ring in Determining Bryostatin-like andPhorbol 12-Myristate 13-Acetate-like Properties

摘要

The seco-B-ring bryostatin analogue, macrodiolide >WN-1, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C–C coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a C2-symmetric diol to form the C9-deoxygenated bryostatin A-ring. >WN-1 binds to PKCα (Ki = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the >WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like behavior, >WN-1 displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in >WN-1, and that upon docking >WN-1 into the crystal structure of the C1b domain of PKCδ, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity.