| Description |
Bryostatin 1 is a complex natural product isolated from the marine bryozon Bugula neritina by Pettit and coworkers whose structure was reported in 1982. This highly oxygenated macrolide has complex and unprecedented architectural features. In addition, bryostatin 1 has exhibited a remarkable biological profile including anticancer activity, synergetic effect with other anticancer agents, reversal of multidrug resistance, stimulation of the immune system, improvement of learning and memory, neuroprotection after stroke, reduction of amyloid plaque formation, and activity against HIV. The anticancer activity of bryostatin 1 has resulted in some 80 phase I and II clinical trials and a clinical trial against Alzheimer's disease is underway. Despite having potential as a therapeutic drug, the availability of bryosatin 1 from natural as well as other sources is extremely limited. Synthesis of simplified analogues of bryostatin 1 provides an alternative way to solve the supply problem. With an aim of practical synthesis of simplified bryostatin 1 analogues, our group started the study of structure activity relationship of bryostatin 1 using a newly discovered pyran annulation methodology. The work presented in this dissertation focuses on the synthesis, computational study and biological evaluation of bryostatin 1 analogues modified in the A and B ring region. Specifically, the role of three substituents in the A and B ring region has been investigated by synthesizing C30-decarbomethoxy bryostatin 1, C9-deoxy bryostatin 1 and a C8-gemdimethyl analogue. This study suggested that these three groups do not by themselves serve as functional switches between the PMA versus bryostatin 1 like activity of bryostatin analogues. Moreover, analogues with more polar groups in the A, B ring region tend to behave like bryostatin 1 as opposed to PMA and vice versa. In addition to bryostatin analogues, the first total synthesis of bryostatin 1 was accomplished in 30 steps for longest linear sequence from commercially available starting material. The synthesis involved a highly convergent union of fully functionalized A and C rings by pyran annulation. The route developed to bryostatin 1 is also applicable for the synthesis of bryostatin 7, bryostatin 9 and bryostatin 15 as well as numerous bryostatin analogues. |
