Bryostatins A and

Because only very limited quantities of Gulf of California L. iso-dictyalis were available from recollections made at various times from 1976-1978 and because of the substantial challenges involved in isolating what appeared to be a series of complex antitumor constituents present in only trace amounts, all efforts to solve this problem until 1982 were unrewarding. During a 1976 expedition we explored some 1500 miles of 

Marine animal Amount (wet wt kg) Bryostatins (mg) 4 5 6 7 8 A B Location (date) 

---

Bryostatins A and B isolated from the sponge Lissodendoryx isodictyalis are respectively deoxybryostatins 5 and 4 (Pettit ef a/., 1986a). Starting from 108 kg ot sponge 0.9 and 0.7 mg of bryostatins A and B were obtained. As for nenstatin 1.8 mg was isolated from one ton of Bugula neritina Petiit et al., 1991b). 

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.

Berkow RL, Kraft AS (1989) Bryostatin, a nonphorbol macrocyclic lactone activates intact human polymorphonuclear leukocytes and binds to the phorbol ester receptor. Biochem Biophys Res Commun 131 1109-1115... 

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. 

Several compounds effectively inhibit Pgp, competitively or noncompetitively. These include verapamil, R-verapamil, cyclosporin-A, PSC 833, LY 335979, GF 120918, S 9788, and RU-486 (82). Another possibility for interaction with Pgp is at its glycosylation sites. Pgp has three glycosylation sites however, blocking of these sites with tunicamycin did not change its efflux function (83). In addition, there are various phosphorylation sites at Pgp that are phosphorylated by protein kinase A and C (84). Application of protein kinase C (PKC) inhibitors resulted in increased accumulation of Pgp substrates (85), whereas phorbol esters stimulated its phosphorylation and increased drug resistance (86). However, the problem with PKC inhibitors is that these compounds are not specific for one PKC isoenzyme. In addition, the PKC inhibitor bryostatin leads first to activation of PKC and later to a downregulation of PKC. For these reasons, PKC modulation has led to many contradicting results (87). 

Fig. 7. Clinical candidates from plants and marine environment Huperzine A, didemnin B, bryostatin 1, and ecteinascidin 743.

The ability to make unnatural cephalostatins will greatly aid our understanding of the biological potency of these compounds. For example, one half could be kept identical to a natural product, while varying the other with synthetic steroids prepared from commercially available materials. In this sense, the cephalostatins provide a unique opportunity for such experiments, as the steroid skeleton is a readily accessible and well understood scaffold in which the effects of particular substituents can be determined. The situation here is in stark contrast to certain other potent biologically active compounds such as taxol (which promotes microtubule assembly) and bryostatin (a protein kinase C inhibitor). In the latter cases, construction of the skeletal framework is a formidable enterprise, hindering further dissection of the biological activity. 

Wender, P.A., Lippa, B., Park, C.-M., Irie, K., Nakahara, A. and Ohigashi, H. (1999) Selective binding of bryostatin analogs to the cysteine rich domains of protein kinase C isozymes. Bioorg. Med. Chem. Lett. 9 1687-1690. 

Aldol reactions are ubiquitous in synthetic organic chemistry to generate intermediates of antihypertensive dmgs and calcium antagonists. Chiral p-hydroxy carbonyl compounds can readily be converted to 1, i-syn and anfr-diols and amino alcohols, which are the building blocks in many natural products such as antibiotics and pheromones and in many biologically active compounds. Aldol products have successfully been converted to key synthetic intermediates of epithilone A and bryostatin 7. ... 

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). 

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). 

---