T1 - Toward the total synthesis of bryostatin 11

Floreancig, Condensation and Commentary on: "Total Synthesis of (")-Taxusin", CHEMTRACTS--ORGANIC CHEMISTRY, 1998, 11, 16.

T1 - Synthesis and biological evaluation of fully synthetic bryostatin analogues

Bryostatin 1 is a marine pyran ­isolated from B. neritina. The family has become popularsynthetic targets due to their molecular complexity as well as theiractivity against a range of cancers and potential activityagainst Alzheimer’s disease. There have been six synthesesof members of the bryostatin family; however, this is the firstsynthesis of bryostatin 1 using a very convergent strategy witha longest linear sequence of 30 steps.

Chapter 5 details the total synthesis of bryostatin 1.

“Towards the Asymmetric Synthesis of Bryostatin 1.”  68.3 (1996): 715–718.

These greatly simplified compounds remove bryostatin's complex northern region entirely by replacing the A- and B-rings with a short diester chain, thus reducing a 20-membered macrocycle to a 14-membered one, and are synthesized in only 19 linear steps (20 total).

Total synthesis of bryostatin 1: a short route.

N2 - The mechanism of tumor promotion may involve stimulation of prostagladin production. Previous studies with the tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) have identified two effects of TPA on prostaglandin production. TPA stimulates both arachidonic acid release and de novo synthesis of prostaglandin H synthase. Activation of protein kinase C by TPA appears to be part of the mechanism to cause archidonic acid release. However, it is unclear if induction of prostaglandin H synthase also involves activation of protein kinase C. Bryostatin 1 is known to activate protein kinase C and to mimic some of the effects of TPA. We compared bryostatin 1 with TPA for the ability to cause arhidonic acid release and induced synthesis of prostaglandin H synthase. Bryostatin 1 induced arachidonic acid release and caused some prostaglandin production but only marginally induced synthesis of prostaglandin H synthase. Furthermore, we found that bryostatin 1 could inhibit the effect of TPA both in stimulation of arachidonic acid release and in the induction of prostaglandin H synthase.

Total Synthesis of Bryostatin 16

Bryostatin 1 activates HIV-1 gene replication through an NF-κB-dependent pathway in chronically infected macrophage cell lines (Qatsha et al., 1993; Vlach and Pitha 1992), and downregulates the expression of CD4 in T cell lines (Boto et al., 1991). Indeed, reactivation of HIV-1 latency in T and other lymphoid cells requires cell activation and it has been demonstrated that Bryostatin 1 activates resting humans' T cells (Trenn et al., 1988) and enhances the maturation of human dendritic cells through a PKC-dependent pathway (Do et al., 2004).

Total synthesis of bryostatin 1 | Read by QxMD

That bryostatin 1 has already been tested in human trials increases its appeal as a target and underscores the need for a reliable supply of a more effective agent. In fact, patient accrual in a recent National Cancer Institute clinical trial with bryostatin 1 was terminated given the awareness of the clinical investigators of more potent bryostatin analogs in development. Research on and clinical studies of bryostatin has been impeded by its low natural abundance. Isolated yields from natural sources are low (10-3 to 10-8 %) and variable; the good manufacturing practices (GMP) production required 14 tons of the marine bryozoan Bugula neritina to provide just 18 grams of bryostatin 1. While this supply was sufficient to initiate preclinical and clinical research, environmental and economic factors have severely limited further development of the source organism and its aquaculture production. Furthermore, while a superb lead, bryostatin suffers from off-target toxicities that have been revealed in clinical studies.