Bryostatin 10 acetate

Table 3. H-NMR Chemical Shift Assignments for Bryostatin 4 Acetate and Bryostatin 10 Acetate (400 MHz, CdCl3)...

As illustrations. Tables 2 and 3 list assignments for the H-NMR spectra of two important bryostatins and two bryostatin acetates while Fig. 5 lists assignments for the C-NMR spectrum of bryostatin 12. Fig. 6 shows the ultraviolet spectra, while mention of other ultraviolet, infrared, and mass spectral characteristics has already been made in Section 5. However an illustration of the application of mass spectrometry to the structure elucidation of bryostatins 5-7 will be instructive (27). The solution phase secondary ion mass spectra of these three bryostatins were quite revealing when new techniques for detecting molecular ions of hitherto refractory substances were utilized. By employing an alkali metal iodide such as sodium iodide or silver tetrafluoro-borate or thallium tetrafluoroborate in sulfolane the molecular ions... 

This material is converted to bryostatin 1 in 11 steps, including Yamaguchi macrolactonization, installation of the B-ring enoate using Fuji s chiral phosphonate [38] and, remarkably, selective hydrolysis of the C20 acetate in the presence of Cl-macrolide, C7 acetate, as well as the Cl3 and C21 enoate moieties (Scheme 5.6). 

Elaboration of triol 88b to bryostatin 7 requires chemoselective hydrolysis of the Cl methyl ester in the presence of the C7 and C20 acetates, macrolide formation, installation of the C13 and C21 methyl enoates, and, finally, global deprotection. The sequencing of these transformations is critical, as attempts to introduce the C21 methyl enoate to form the fully functionalized C-ring pyran in advance of macrolide formation resulted in lactonization onto the C23 hydroxyl. In the event, trimethyltin hydroxide promoted hydrolysis [73] of the Cl carboxylate of triol 88b, and subsequent trie thy lsilylation of the C3 and C26 hydroxyls each occurs in a selective fashion, thus providing the seco-acid 89. Yamaguchi macrolacto-nization [39] proceeds uneventfully to provide the macrolide 67 in 66 % yield (Scheme 5.14). 

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1). 

By extraction from 1000 kg of Bugula neritina 906.5 g of lymphocytic leukemia cell line active fraction was obtained. Further purification was performed with HSCCC. Bryostatins have intermediate polarity, so that n-hexane-ethyl acetate-methanol-water (3 7 5 5,... 

Other approaches to the bryostatins have also used enantio- or diastereoselective aldol reactions. An interesting iterative strategy for the synthesis of the Cj-Cg polyacetate region 134 has been disclosed where each aldol addition proceeds with excellent stereocontrol (99 1) under the catalytic influence of oxazaborolidine 135 (Scheme 9-42) [60J. Finally, a moderately selective, auxiliary controlled, acetate aldol reaction has been used for the introduction of the C3 stereocenter of the bryostatins giving adduct 136 (84% d.s) [61]. 

Bryostatin 1 increased the susceptibility of U-937 cells to taxol-induced apoptosis and inhibition of clonogenicity (Wang et al. 1998). Bryostatin induced multiubiquitinylation of protein kinase C-a in vitro and in renal epithelial cells (Lee et al. 1996). In vitro multiubiquitinylation required ATP (or ATP6S), membranes containing the 76-kDa, nonphosphorylated form of protein kinase C, and a cytsol fraction (Lee et al. 1996). In primary cultures of human dermal fibroblasts bryostatin 1 and phorbol myristate acetate down-modulated protein kinase C-a and -e via the ubiquitin/proteasome pathway (Lee et al. 1997). 

In NHI 3T3 fibroblasts bryostatin 1 showed similar potency to 12-0-tetradecanoylphorbol-13-ace-tate for translocating PKCa to the cell membrane but was a much more potent downregulator of PKCa activity than 12-0-tetradecanoylphorbol-13-acetate. It was also a much more potent translocator and downregulator of PKC8 and PKCe than 12-0-tetradecanoylphorbol-13-acetate (Szallasi et al. 1994). The compound inhibited the proliferation of human A549 lung carcinoma (Dale and Gescher... 

Bryostatins, unlike 12-0-tetradecanoylphorbol-13-acetate do not include monocytic differentiation of HL-60 cells (Kraft et al. 1986). They bind to the phorbol esterbinding sites in human neutrophils and HL-60 cells, activate purified protein kinase C, induce protein phosphorylation patterns similar to 12-0-tetradecanoylphorbol-13-acetate, and induce... 

Bryostatin 1 could inhibit the effect of 12-0-tetradecanoylphorbol-13-acetate both in stimulation of [ Hjarachodonic acid release and the induction of prostaglandin H synthase in Madin Darby canine kidney cells cultivated in Dulbecco s modified Eagle s medium (Parker et al. 1988). 

Both bryostatin 1 and 12-0-tetradecanoylphor-bol-13-acetate inhibited lymphocyte antibody-dependent cell-mediated cytotoxicity such that, at a 20 1 effector-to-target ratio, control lymphocytes had a mean 49 12% specific Cr release of antibody-coated target cells while bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate cultured lymphocytes had 12 6 and 8 12%, respectively, in four experiments (Tilden and Kraft 1991). 

McBain, J.A., G.R. Pettit, and G. Mueller Bryostatin 1 Antagonizes the Terminal Differentiating Action of 12-0-Tetradecanoylphorbol-13-acetate in a Human Colon Cancer Cell. Carcinogenesis 9, 123 (1988). 

Dale, I.L., T.C. Bradshaw, A. Gescher, and G.R. Pettit Comparison of Effects of Bryostatins 1 and 2 and 12-0-Tetradecanoylphorbol-13-acetate on Protein Kinase C Activity in A549 Human Lung Carcinoma Cells. Cancer Res. 49, 3242 (1989). 

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