Bryostatins

However, in contrast to phorbol esters, bryostatins do not act as tumor promoters. In many systems bryostatin 1 induced only a subset of the responses to TPA and sometimes blocked those which it did not induce (Blumberg, 1991). 

When we found 4) that extracts of the marine bryozoan Bugula neritina L. exhibited exceptional antineoplastic activity (100% life extension) against the PS lymphocytic leukemia we proceeded with an extensive investigation of this animal and 14 years later reported (77) the 

From evidence now in hand, Bugula neritina indigenous to the U.S. West Coast seems to have a special ability for synthesis of the C-20 ( , E)-octa-2,4-dienoate ester. While no evidence for even trace amounts of bryostatins 1-3 could be detected in the various Gulf specimens of Bugula neritina, we were able to find barely detectable (by thin layer chromatography) amounts of bryostatins 4-7 in the Eastern Pacific Bugula neritina. The trace amounts (tic only) of bryostatins 4-7 came from about 500 kg (wet wt.) of California B. neritina. 

As emphasized above in the summary of A. convoluta research, B. neritina contains very potent antineoplastic constituents with the capacity to intrude upon or otherwise become associated with certain other marine organisms. Therefore, the possibility of Bugula contamination should be considered prior to selecting a new marine animal for detailed chemical study directed at isolation of possible antineoplastic constituents. 

Aside from the capricious result of the A. californicum research the tunicates in general represent a productive source of new antineoplastic substances (for leading references consult 23)). Indeed, during our initial (1965-1968) worldwide evaluation of marine animals as sources of new anticancer substances, we uncovered the first tunicates (e.g., Styela plicata) with such constituents (4). On our Institute s 1976 expedition to the coast of Honduras, we located a very promising [NCI confirmed active, T/C 173 (9.37 mg/kg)] tunicate of the Trididemnum genus that was later found independently by A. J. Weinheimer and colleagues to yield potent antineoplastic cyclic depsipeptides (the didemnins). 

The accelerating interest arising from the remarkable biological properties displayed by bryostatins 1 and 2 encouraged us to look for 

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Bryamycin Bryostatin 1 BSA-SILICA B-stage B-stage resins B. subtilis 66333 BTEPE [37853-59-1]... 

Bryostatins are another class of compounds that bind to the Cl domain and result in acute activation of PKC. However, unlike phorbol esters, these marine natural products have antitumor effects. Bryostatins are currently in phase II clinical trials and show promise as anticancer drugs, particularly when combined with other adjuvant therapy. 

Figure 3.3. Bryostatin 2. Bryostatin 2 (C HggOjg) is a biologically active marine natural product which may have useful anti-cancer properties. It was recently synthesised at Harvard by Professor David Evans and his research group. In this illustration, all of the hydrogen atoms are omitted in order to simplify the structure. The lower diagram shows a low energy conformation of bryostatin 2, but it may only be a local minimum and not a global minimum. Many other conformations are accessible at room temperature.

Figure 3.4. Pentane. The diagram shows the four minimum-energy conformations of pentane. The global minimum is on the far left. Reflection and rotation of some of these geometries worrld generate more structures, but nothing with a different energy. Pentane is a simple molecule. More complicated molecules have many more conformations. Bryostatin 2 and PM-toxin A have so many mirrimtrm-energy conformations that to list them all would be a major undertaking and would require a large library to store the result.

The structures of the bryostatins were determined by a combination of singlecrystal X-ray diffraction analysis and/or a series of detailed spectroscopic analyses. 

As described in several monographs [4], bryostatin 1 exhibits significant in vitro and in vivo antineoplastic activity against a range of tumor cell lines including murine leukemia, B-cell lymphoma, reticulum cell sarcoma, ovarian carcinoma, and melanoma. It is also effective in the modulation of apoptotic function [5], the reversal of multidrug resistance [6], and stimulation of the immune system [7]. These unique features displayed by bryostatin 1 are attributed to its high affinity for protein kinase C (PKC) isozymes and its ability to selectively modulate their functions [8]. PKCs are a type of intracellular serine and threonine kinase that... 

C1, C19, C26 pharmacophoric element C3, C11 transannular hydrogen bonding C7, C20 tunable substituents C8 gem-dimethyl crucial for bryostatin-like biological respose... 

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