Bryostatins 12 and

In order to isolate and structurally identify the remaining bryostatins earlier detected only in microgram or less quantities and to obtain enough bryostatin 1 for homonuclear correlation (COSY), two dimensional carbon-proton chemical shift correlations ( H- C 2D), 2D-J-resolved experiments, proton-proton differential nuclear Overhauser enhancement (NOEDS, or H-[ H] NOE) experiments, and additional biological evaluation, a 4000-L recollection (1981) of Bugula neritina 

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Two recent exemplary applications in organic synthesis employing either a rhodium(l)/BlPHEHOS or a rhodium(I)/XANTPHOS catalyst to achieve a linear-regioselective hydroformylation of terminal aUcenes are summarized in Schemes 10 and 11. The hydroformylation of an aldehyde allylation product has served as a key step diu ing the course of a synthesis of a BC-ring subunit of the anticancer agent bryostatin (Scheme 10) [55]. 

A Study of some chemical transformations was required to complete structure determinations of bryostatins 4-11. Use of 1% hydrochloric acid in methanol provided a method for fairly selective hydrolysis of the C-7 ester substituent. However, with bryostatin 10 (10) a new reaction pathway was uncovered. Key reactions and spectral interpretation used to dedpce the structure of bryostatin 10 are illustrative (28) of our experience to that time. 

Parallel results were found when bryostatins 4 and 10 were allowed to react with m-chloroperbenzoic acid in methylene chloride at room temperature. Introduction of one oxygen atom required two days. The SP-SIMS spectra were consistent with an additional 16 mass units, but while epoxidation of bryostatin 4 occurred at the A -olefin, epoxidation of bryostatin 10 occurred at the A -olefin, a conclusion reached by considering the H-NMR spectra. The spectrum of bryostatin 10 epoxide retained the olefinic resonances of the A double bond but the H-30 olefinic resonance at 85.658 was shifted to higher field at 53.358, a shift characteristic of hydrogen on an epoxide. In addition, the C-36 methyl... 

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

By 1987 we had substantial evidence that bryostatins 1 and 2 reacted in a synergistic fashion with recombinant B-cell stimulatory factor/inter-leukin 4 to stimulate resting T-cells to proliferate and differentiate into cytotoxic T-lymphocytes (62). At the same time interleukin-2 (IL-2) development of cytotoxicity was greatly enhanced (62, 63) suggesting that the bryostatins may allow the clinical dose of the hazardous recombinant IL-2 to be considerably reduced. In a related study concerned with the effects of bryostatin 1 on IL-2 and y-interferon synthesis by ionophore A23187 or mitogen-induced human blood lymphocytes we found the production of these two lymphokines to be increased 10-100 fold (63). Interestingly, bryostatin 1 was also found (64) to effectively block T-cell proliferation induced by a phorbol (PMA). 

Research results summarized in Sections 8-10 strongly indicate that bryostatin 1 and/or others in the series may prove to be clinically useful for treatment of cancer and certain other medical problems. Recently, bryostatin 1 has been found to inhibit six of seven fresh human myeloid leukemia specimens 74 prevent (whereas the phorbol PMA induces) squamous differentiation in human tracheobronchial epithelial cells (75), inhibit A549 human lung carcinoma cells 76) and very importantly induce differentiation of human B-chronic lymphocytic leukemia (CLL) cells (77, 78). The latter important contribution by Drexler and colleagues may open a clinical path to successfully treating the routinely fatal CLL. 

Kamano, Y, Zhang, H.-P., Hino, A., Yoshida, M., Pettit, G.R., Herald, C.L., and Itokawa, H. (1995a) An improved source of bryostatin 10, Bugula neritina from the gulf of Aomori, Japan. J. Nat. Prod., 58,1868-1875. 

Marine organisms represent a largely unexplored source of unique toxic chemicals. These toxins are produced by the organisms as defense weapons against their predators. Several potent compounds demonstrating antitumor activity in vitro and in vivo have been isolated from marine organisms, e. g., the bryostatins (from Bugula neritina), dolastin 10 (from Dolabella auricularia) and halichondrine B (from Halichondria okadat) [61]. 

Although these compounds are all anticancer agents, they act through different mechanisms. Bryostatin 1, a cyclic macrolide, inhibits protein kinase C tumor promotion while aplidine is a protein synthesis inhibitor. Dolastatin 10, a linear peptide, and ET743, a tetrahydroisoquinoline... 

Peloruside A 14 (Scheme 6.1 Part 2) was isolated from a New Zealand Mycale hentschei marine sponge and initially showed activity against P388 murine leukaemia cells at 10 ng/mL.98 Peloruside s cytotoxicity profile and structural similarity to bryostatin led to the examination of protein kinase C (PKC) as a possible mode of action.242 This was determined to be incorrect and it was soon established that the remarkable activity of peloruside was through the stabilisation of microtubules at a site distinct from the taxoid site.243... 

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