REVIEW ARTICLEChemistry and clinical biology of the bryostatins
Introduction
The bryostatins are a class of highly oxygenated marine macrolides with a unique polyacetate backbone. Bryostatin 1 (Figure 1, Figure 2) was first isolated and characterised by Pettit in 1982,1 from the marine animal Bugula neritina (Linnaeus), after showing high activity against the murine P388 lymphocytic leukemia. Currently, there are 20 natural bryostatins (Fig. 1) known; their main difference being the nature of the substituents at C7 and C20.2
Since their discovery, bryostatins have created a wide interest in the scientific community. The antineoplastic activity, in combination with low toxicity, has made this class of compounds a chemotherapeutic candidate for the treatment of cancer. The specific interactions with protein kinase C (PKC), and other enzymes, led to a wide range of studies directed towards a better understanding of its specific activity as well as clarifying the mechanism of action of cellular signalling pathways in general. The limited supply and the low concentration in the natural source yielded an investigation of the marine animal and attempts to cultivate it. The unique chemical structure of the bryostatins posed a major synthetic challenge and its current market price at £261 (UK)/50 μg3 has definitely created business interest. In this review we attempt to give an overview of the different aspects of research involving bryostatins and a summary of the latest results. Some topics are previously reviewed and mentioned in the appropriated section of this review.
Section snippets
Natural sources and biosynthesis
The first collection of Bugula neritina from the Gulf of Mexico in 1968 led to the isolation of bryostatin 1,1 the major active substance in the animal. Further and larger collections yielded in the isolation of bryostatins 2,4 3,5 4,6 5–7,7 8,8 9,9 10+11,10 12+13,11 14+15,12 and 16–18.13 The first published structure of bryostatin 3 was later revised.14 Another collection from the same location led to the isolation of bryostatin 4 in 8.9×10−5% wt yield. Collections from the Gulf of California
Cultivation of bryozoans
Bugula neritina is commonly used in the laboratory and in field studies because of its abundance and the ease with which the larvae can be collected and induced to ‘settle’/adhere to a surface in the laboratory.18 The larvae are nonfeeding and spend only a few hours in the water before settling. Studies on the effect of swimming duration, settling and growth of the larvae were carried out under laboratory conditions21 as well as under field conditions.22 The general outcome was that larvae
Bioactivity
Bryostatin 1 has a wide range of activities including immune stimulation, growth inhibition, induction of differentiation, and enhancement of cytotoxicity of other drugs particularly towards target cells.25
A wide range of studies on the molecular and cellular level was carried out involving bryostatins. They can be split into two general groups: studies designed to understand the action of bryostatins on enzymes and cell lines and studies designed to gain a better understanding of enzyme
Molecular interaction
The family of protein kinase C isoenzymes are serine/threonine kinases comprising 12 isozymes that play crucial roles in various cell-signalling and other processes.
Diacylglycerols (DAG), phosphatidyl serine (PS), inositol triphosphate (IP3) and calcium ions (Ca2+) are the naturally occurring activators of these enzymes. The PKC group of kinases transfers the terminal phosphate from adenosine triphosphate (ATP) onto other proteins, and in some reactions self-phosphorylation occurs. To activate
Cellular interaction
In almost all studies the action of bryostatin 1 on PKC-isoforms was investigated. The general outcome is that bryostatin 1 induces an initial short lasting activation and self-phosphorylation of PKCs leading to its translocation to the membrane and subsequent down-regulation by induced proteolysis by a proteasome. Beside this commonly reported observation, studies focus on diverse range of aspects and effects on different proteins. Many contradictory results have been reported and it seems
Results of preclinical studies and of clinical trials
The preclinical and clinical aspects of bryostatin 1 was recently reviewed by Zonder and Philip.72
Several preclinical studies were undertaken to understand how bryostatin 1 might be best used as an anticancer drug. The pharmacokinetics, tissue distribution, metabolism, and elimination of bryostatin 1 in CD1/F2 mice were studied,73 using [C26-3H]-labelled bryostatin 1. The half-lives after iv administration were 1.05 h and 22.97 h. Similar results were obtained after ip administration. There was
Synthesis
Several groups have contributed towards the synthesis of bryostatin and some work remains to be published. The structure has led to the development of a number of new reactions and many different disconnection strategies have been applied. Often the strategies have had to be modified during the work because of unexpected problems arising from unstable intermediates or from problems with the final coupling steps.
This part of the review describes the latest developments in the synthetic work on
Evans' total synthesis of bryostatin 292,93
The disconnection that was employed for the total synthesis of bryostatin 2 (Scheme 1) features the introduction of some of the functional groups as well as the removal of the protecting groups (Disconnection 1). The macrocyclic intermediate was formed from three cyclic segments (Disconnection 2). Using more complex segments, which would simplify the first disconnection, proved to be unsatisfactory because of low yielding coupling reactions.
C1–C9 segment (Scheme 2)
The dibutylboron triflate-mediated aldol reaction
Kalesse's C1-C9 segment synthesis94 (Scheme 7)
Addition of ethyl acetoacetate to propargylic aldehyde (54) gave racemic hydroxy ketone, which was benzylated and desilylated to β-keto ester (55). Bakers' yeast kinetic resolution led to β-hydroxy ester (56) in a de of 82% and an ee of 84%. Better de and ee's were obtained with different protecting groups, but the benzyl-protecting group was chosen because of its stability under the Sakurai conditions. Hydrogenation of the acetylene moiety followed by reduction and silylation led to the
Studies towards analogues
Bryostatins have a limited availability, the extraction from the natural sources is complex and there is no commercially viable total synthesis of any of the molecules. Therefore, methods to make simplified analogues are an attractive way to solve the supply problem. Knowing the general pharmacophore model of the PKC enzyme and the groups in bryostatin, to which it binds, Wender and co-workers started to study the matter closely. Recently, he reviewed his work,102 and therefore we present only
C17–C27 segment synthesis (Scheme 13)
Aldol condensation of the dieneolate of (117) and aldehyde (118) followed by acid-catalysed cyclodehydration gave a 1:1 mixture of dihydropyranones (119a,b). The β-isomer was reduced using Luche conditions, the resulting glycal was deoxidised and the ring opened followed by selective benzoylation and oxidation to afford ketone (120). Deoxygenation gave ketone (121), which was transformed to E-enone (122) via aldol addition, mesylation and elimination. Selective reduction using Luche condition
Acknowledgements
We would like to thank Sandra Van Meurs, Professor Timothy D. H. Bugg and Dr. Peter Critchley for their help and assistance.
Martin Wills was born in Swansea in 1964, and grew up in Swansea, Cardiff and Reading. He completed a BSc at Imperial College, London in 1982 and a DPhil at Oxford University under the supervision of S. G. Davies in 1985. Following a year of postdoctoral research with the late W. Oppolzer at Geneva he was appointed to a lectureship in organic chemistry at Bath University. In 1995 he moved to a readership at Warwick University, where he is currently working on the development of novel asymmetric
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Martin Wills was born in Swansea in 1964, and grew up in Swansea, Cardiff and Reading. He completed a BSc at Imperial College, London in 1982 and a DPhil at Oxford University under the supervision of S. G. Davies in 1985. Following a year of postdoctoral research with the late W. Oppolzer at Geneva he was appointed to a lectureship in organic chemistry at Bath University. In 1995 he moved to a readership at Warwick University, where he is currently working on the development of novel asymmetric catalysts and synthetic methodology. Dr. Wills was the winner of the 1993 Meldola Medal and Prize of the Royal Society of Chemistry and the 1999 GlaxoWellcome Prize of innovative synthesis. He is honoured to have been associated with so many talented current and former postdoctoral reseachers and postgraduate students with whom a vigorous programme of research into asymmetric catalysts and total synthesis is flourishing at Warwick.
Roger Mutter originates from Niederwald (Switzerland) and was born in 1971 in Sion. After completing an apprenticeship as laboratory assistant at Lonza Ltd in Visp he moved on to the Institute of Technology in Sion, where he obtained a BSc in chemical engineering. He then rejoined Lonza Ltd on a temporary basis as assistant to the team leader, validating an in-house built LIMS-program. In 1997 he joined the research group of Martin Wills as a self-funded student. He was working on the synthesis of bryostatin analogues and obtained an ORS Award for his second and third year, During his study he was given the opportunity to enjoy an industrial placement at Norvartis Ltd Basel, where he was working under supervision of Dr. Karl-Heinz Altmann on the synthesis of epothilone analogues. A second placement at GlaxoWellcome Ltd in Stevenage under supervision of Dr. Andy Merritt led him into the field of parallel synthesis. He will finish his PhD in summer 2000. His main research interests are medicinal chemistry.