Bryostatin derivatives

Although, for example, tetracyclic terpenoid lactones (Figure 3.9.1) have been found,88 the main bryozoan metabolites of interest are alkaloids and macrocyclic ethers.89 The tambjamines are a good example of alkaloids. These are bipyrolles that occur in ascidians as well as in nudibranchs that derive them from eating ectoprocts, ascidians, or even other nudibranchs (see section below on Urochordata). The bryostatins (Figure 3.9.2) are the important polyethers from ectoprocts.90 They are macrocyclic lactones. 

Bryostatin 7 (3) was the first member of the bryostatin family that was accessible by total synthesis. Its preparation was described by Masamune et al. already briefly after its isolation from Bugula neritina [8]. Their concept was based on a combination of the four synthons 4-7 (Figure 2) The (R,R)-2,5-dimethylborolanyl triflate mediated aldol reaction of aldehyde 4 with the enolate derived from ketone 5 leads after a sequence of deprotection steps, cycliza-... 

Bugula neritina) and related organisms produce substances with antibacterial, antitumor (e.g. bryostatins, didemnin B, dolastatin, girodazol, halichondrin B), anti-inflammatory (e.g. pseudopterosin E, manoalide derivatives), antifungal, antiviral, or immuno-suppressive (e.g. microcolin A and B) activity [399,400]. These compounds and/or their synthetic derivatives may be important novel bioactive pharmaceutical substances. It is also very Hkely that some new natural marine substances or their derivatives can be used as antifouling compounds, insecticides, or fungicides. 

Figure 1 Structures of marine-derived secondary metabolites which have entered clinical trials or which are used commercially. 1 (ecteinascidin 743), 2 (aplidine), 3 (dolastatin 10), 4 (bryostatin 1), 5 (pseaudopterosin E)...

Bryostatins are naturally occurring antineoplastic macro-cyclic lactones derived from the marine invertebrate Bugula neritina, different varieties being isolated from different populations of the same species. More than 13 structurally related compounds have been isolated (1,2), and there is a variety of synthetic analogues (3). The bryostatins modulate the activity of protein kinase C. 

Polymer-supported enzymes have been combined with polymer-supported reagents in the synthesis of the bryostatins. The nitrone derived from the nitro compound 43 supported on a soluble aryl poly-ether polymer undergoes an efficient 1,3-dipolar cycloaddition with butenone to give the isoxazoline 44 and hence by reduction the racemic syn compound 45 required for the synthesis.16... 

The sea covers almost three-quarters of the earth s surface and contains a broader genetic variation among species relative to the terrestrial environment (155,158).Althoughanum-ber of important molecules have been derived from marine sources, including arabinosyl nucleotides, didemnin B, and bryostatin 1, there has been an inadequate focus on this potentially chemically productive biosphere. Sea snails, often called "nature s combinatorial chemistry factories," produce a bewildering array of novel conotoxins active at mamma-... 

Application of the external chiral boron reagent (90) in the totd synthesis of bryostatin, a natural product, is shown in Scheme 45. The convergent approach adopted involves coupling of the boron enolate derived from (111) with aldehyde (112). The reaction mediated by an achiral boron reagent (Et2BOTf) provides only a 2 1 preference for the formation of the desired isomer (115) in adduct (113). The use of chiral (2/ ,5 )-dimethylborolanyl triflate in this reaction increases the selectivity to a 6 1 preference as... 

Earlier, some of the same considerations had led me in 1957 to initiate a study of amphibian venoms of the steroidal bufadienolide (6) type as potential sources of new antineoplastic substances. Eventually we found that some of the toad venom bufadienolides such as marinobufagin significantly inhibit growth of the National Cancer Institute s KB cell line derived from a human nasopharynx carcinoma and lead to a curative response with the murine Ehrlich ascites system (7). However, the therapeutic indices were unattractive for further development. So the effort was extended in 1965-66, as Just noted, to encompass a geographically far-reaching area (Asia, Africa, Australia etc.) and an extensive research program to evaluate marine invertebrates and arthropods for structurally unique and useful anticancer constituents. Subsequently we isolated the first such invertebrate antineoplastic constituents (8-12). Meanwhile, our early expectations have been abundantly realized and the discovery of the bryostatins provides a splendid illustration. 

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