Bryostatin structures

The crystal structure determination (77) of bryostatin 1 in 1982 and the interpretation (29) of the corresponding high field (400 MHz) NMR spectra formed the basis for all subsequent bryostatin structure determinations. All 400 MHz H-NMR spectra of the bryostatins until about 1986 were measured using an early model of the Bruker 400 instrument and required coupling assignments by hand. Hence some minor adjustments in the early proton assignments have already been found necessary. 

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. 

Only transformations in the longest linear sequence (LLS) are considered. The term skeleton constructions refers to C-C and C-O bond formations (notwithstanding redox reactions) that directly introduce native structural features of the bryostatins without further modification. The term other functional group manipulations refers to steps that indirectly introduce native structural elements, the interconversion of functional groups (e.g., the introduction and removal of auxiliaries) and miscellaneous transformations that do not involve skeleton construction... 

Protein kinase C (calcineurin) Bryostatin 1 (Structure 16.9) Bryozoan, Bugula neritina Anticancer20... 

Fig. 1. Molecular structures of bryostatin natural products which are accessible by total synthesis.

Obviously, the access to the A, B and C ring fragments is the key to a successful synthesis of bryostatins. Therefore, next to the total syntheses several partial syntheses [18] and preparations of ring fragments are reported [19], These partial structures are also valuable components regarding the synthesis and evaluation of bryostatin analogues. 

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... 

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. 

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]. 

Further bioassay-guided examination of a Gulf of Mexico collection of Bugula nerttina has yielded neristatin 1, 19, the first bryostatln biosynthetic precursor or degradation product to be reported. Neristatin 1, whose structure was determined by a combination of spectroscopic and X-ray diffraction data, is antineoplastic but is not as active as the bryostatins [17]. 

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