Bryostatin from Bugula neritina

Two additional members of this series have been reported recently from Bugula neritina bryostatin 14, 13, was obtained in 1.02 x 10 %... 

Sudek S, LopanikNB, Waggoner LE, Hildebrand M, Anderson C, Liu HB, Patel A, Sherman DH, Haygood MG (2007) Identification of the putative bryostatin polyketide synthase gene cluster from Candidatus endobugula sertula , the uncultivated microbial symbiont of the marine bryozoan Bugula neritina. J Nat Prod 70 67-74... 

Reeves MR Eberwein RM, Rodgers LL, Testerman RR Snader KM, Forenza S. (1991) The large-scale isolation of bryostatin 1 from Bugula neritina following current good manufacturing practices. J Nat Prod 54 1265-1270. 

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]. 

Bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa [457], They were first discovered in the bryozoan Bugula neritina, but problems with supply of sufficient quantities of this natural product hampered the study of this interesting group of marine metabolites for many years. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for PKC isoenzymes, compete for the phorbol ester binding site on PKC and stimulate kinase activity in vivo and in vitro. Bryostatin 1, Fig. (54), one member of this family, is a PKC modulator in a variety of tumor systems [458,459], Bryostatin 1 is currently in phase II... 

Kerr, R. G., Lawry, J., and Gush, K. A., In vitro biosynthetic studies of the bryostatins, anticancer agents from the marine bryozoan Bugula neritina, Tetrahedron Lett., 37, 8305, 1996. 

FIGURE 3.9 Selected metabolites from bryozoans and a brachiopod. 3.9.1 Securine A from Securiflustra securirons.209 3.9.2 Bryostatin 18 from Bugula neritina,210 3.9.3 Glycerol ethers from the brachiopod... 

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-... 

Bryostatins are medicinally important macrolides discovered from the cosmopohtan bryozoan Bugula neritina (2). Twenty bryostatins, which all possess a 20-membered ring, are known to date. Bryostatin 1 (33) showed good antitumor activity it selectively modulates protein kinase C (12). 

Four compounds are currently under clinical investigation for their use as anticancer agents (Fimre 1). These are ecteinascidin 743 (1), from the tunicate Ecteinascidia turbinateaplidine (dehydrodidemnin B, 2) from the ascidian Aplidium albicans dolastatin 10 (3) from the sea hare Dolabella auratium and bryostatin 1 (4) from the bryozoan Bugula neritina The marine environment has also been the source of a number of anti-inflammatory compounds such as pseudopterosin E, (5). The pseudopterosins constitute the major active components in a popular line of skin care products. ... 

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. 

The bryostatins have been isolated from marine materials, bryozoan Bugula neritina [4] (Fig. 2b). They are macrolides with intermediate polarities. They show significant activity against lymphocytic leukemia in vitro. 

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,... 

An important group of secondary metabolites from bryozoans consists of the macrocyclic lactones which have been obtained from Bugula neritina. These compounds have potential as leads for future anticancer drugs. Bryostatins 1-15 are bryopyran lactones, 1-15, which have very selective antineoplastic and cytostatic activity. Bryos-tatin 1, 1, is undergoing clinical evaluation. Chemical components of B. neritina vary somewhat depending on the area of its collection. The isolation, structural elucidation and biological activity of bryostatins 1-13 have been reviewed [5]. 

There has been very little experimental work conducted with natural products from the phylum Bryozoa. The family of bryostatins, macrolide polyketides isolated by Pettit from the bryozoan Bugula neritina, is certainly of greatest significance in terms of biomedical potential [92]. Bryostatin 1 (57) exhibits selective activity against B-cell lymphomas and leukemias, [93] and directly stimulates bone marrow progenitor cells to form colonies that functionally activate neutrophils [94]. Additionally, bryostatin 1 activates protein kinase C [95] and has immunomodulatory activity both in vitro and in vivo [96]. In combination with the vinca alkaloid vincristine, bryostatin 1 inhibits the growth of lymphoma cells without adverse effects on bone marrow cells [97]. 

Scheme 18. Bryostatin 1 [1] and bryostatin 2 [2] from the marine bryozoan Bugula neritina.

The bryostatins, macrocyclic antineoplastic lactones, have been isolated from another common marine bryozoan, Bugula neritina (154). All 15 bryostatins known so far represent variations over the bryopyran skeleton. Different collections exhibited large variations, quantitative as well as qualitative, in bryostatin content. Bryostatin 4-7 without trace of 1-3 were obtained from some northeastern Gulf of Mexico collections. Some eastern Pacific collections had barely detectable amounts of bryostatin 4-7. Bryostatins have been found in other organisms as well, however in each case association with B. neritina was demonstrated. The marine bryozoan Amathia con-voluta contained bryostatin 4-6 and 8, while the marine sponge Lissodendoryx iso-... 

The bryostatins are a family of potent antitumor agents, among which bryosta-tin 1 (63) was first isolated in 1968 from the bryozoan (sea-mat) Bugula neritina, an innocuous filter feeder that habitually attaches to ship hulls [124, 125]. The structure of bryostatin 1 (63) was determined through X-ray crystallographic analysis and its absolute stereochemistry was defined by heavy-atom dipersion... 

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