The design, synthesis, and biological evaluation of structurally simplified bryostatin and laulimalide analogues

The design, synthesis, and biological evaluation of analogues of two natural products, bryostatin and laulimalide, is reported. Both of these leads show exceptional activity against human tumor cells and act through unique biological mechanisms. The efficiency of the isolation of both these natural products is extraordinarily low, and their structural complexity reduces the prospects of increasing supply through total chemical synthesis. In addition, their therapeutically relevant biological activity is most likely an artifact of their evolutionary use. Using these natural products as a starting point, analogues were targeted with the goal of retaining or enhancing the desired biological activity while eliminating unnecessary structural complexity found in the natural products.; First-generation structurally simplified analogues of bryostatin that are available through practical synthetic routes and that retain and even improve on bryostatin's remarkable activity had been previously reported. The design of these analogues was based on a pharmacophore hypothesis. In order to refine this pharmacophore model, late stage, selective chemical transformations were developed and applied to these analogues. This work resulted in the discovery of a highly chemo- and regioselective C-H oxidation reaction, using dimethyldioxirane, that reinstalls the C9 hemiketal found in bryostatin. Consistent with the pharmacophore hypothesis, reinstallation of this functionality did not provide a significant benefit in affinity for the biological target, PKC. Additionally, a highly chemoselective photoisomerization reaction was applied to quickly explore the role of the bryostatin C21 enoate in the pharmacophore model. The results from this study indicate a key role for this substructure, as all analogues exhibited significantly reduced affinity for PKC.; Structurally simplified analogues of laulimalide, available through improved and more practical synthetic routes, were found to retain the microtubule-stabilizing ability of the natural product. The most potent of this group, 11-desmethyllaulimalide, is nearly as potent as laulimalide itself but is available via a shorter and more cost-effective synthesis.{09}In a separate study, the cross metathesis reaction was used to explore the role of the "side chain" portion of laulimalide. The potency of these analogues, but not the function, was found to be highly dependent on the structure of the C23 side chain fragment.