Convergent syntheses of bryostatins

Over the years, many compounds, natural products, have been isolated from plants, animals and other forms of life, e.g. micro-organisms. Some of these are very toxic but others have proved to be useful leads for the discovery of new pharmaceuticals, e.g. antibiotics such as the penicillins and cephalosporins, and taxol which has emerged for the treatment of certain cancers. About 20 years ago, a new group of very complex natural products, the bryostatins, was isolated from a marine animal, Buluga neritina, a bryozoan filter feeder, although more recently it has emerged that these compounds are actually produced by a micro-organism which cohabits with the bryozoan. The bryostatins were immediately recognized as having potent anti-cancer activity and have been of considerable interest to medicinal and synthetic chemists since. Although some side effects are observed when patients are treated with bryostatins, there are marked improvements when the bryostatins are prescribed in combination with other chemotherapies. The bryostatins have also been found to have many other potentially useful biological activities such as stimulation of the immune system, reversal of damage due to a stroke and memory enhancement in animal models. The actual modes of action of the bryostatins are partly understood although more remains to be done in this area.Notwithstanding these exciting biological activities, there are severe problems in the supply of bryostatins. To date they have been isolated from the natural marine source, but this is environmentally unacceptable and also very unreliable, for example, an aquaculture programme for the production of bryostatins has recently been discontinued. The bryostatins have been synthesized by organic chemists, but the early syntheses were very long and were not convergent, and so did not add to the supply of bryostatins for biological evaluation. More recently bryostatin like compounds have been designed. Some of these possess the activities of the natural bryostatins and are under clinical evaluation.The objectives of the present work are to develop a new and more convergent synthesis of bryostatins which can be used to provide material for biological evaluation. Initially the work will target a sub-group of bryostatins which has not been prepared before. Once the chemistry to achieve this objective has been sorted out, it will be applied to complete syntheses of other bryostatins and simpler analogues for biological evaluation.The synthesis which it is proposed to carry out has been studied for many years. It is hoped to complete the synthesis of a naturally occurring bryostatin in about thirty linear, i.e. sequential, steps. To date the first twenty six of these have been carried out successfully. It remains to find reagents and conditions for the final four steps and then to complete syntheses of naturally occurring bryostatins and analogues.

A completed synthesis of a naturally occurring bryostatin will be recognized internationally by synthetic organic chemists as a major achievement and will help to underpin the reputation of the UK's organic chemistry community. Moreover, the publications on our results in chemical journals will be read by other synthetic chemists in industry and academia and will help them with their own work. The bryostatins have potent anti-cancer activity and have been involved in many clinical trials world-wide. However, the supply of bryostatins from natural sources is very limited indeed. It is proposed to develop a synthesis of bryostatins which will be convergent and less than 30 linear steps long. Such a synthesis could be used to prepare samples of the natural compounds or structural analogues of the natural products for biological studies. This work could then help to lead to a better understanding of the biological mechanisms of action of bryostatins and may even contribute to the development of new chemotherapeutic agents. If this is the case then the work would have a major economic impact. Arrangements are in place with life-scientists in Manchester and Liverpool for advanced intermediates and any analogues prepared to be evaluated biologically. Once a synthesis of a natural bryostatin has been completed, medicinal chemists who have published on PKCs will be approached to see whether our compounds (or chemistry) is of interest to them. Aspects of this programme will be outside the scope of the work which it is expected to be able to complete during the course this grant. Nevertheless our synthesis should be able to deliver either several hundred milligrammes of one natural bryostatin, or an analogue, or it could be used to prepare smaller amounts, say twenty milligramme batches, of several compounds for biological screens. It should be noted that commercial sources of bryostatins are very expensive indeed, ca. 181 for a tenth of a milligramme on one web-site. However, it will be necessary to complete a synthesis of a naturally occurring bryostatin first so that the final stages of the synthesis are understood, before macrocyclic analogues can be prepared. Finally, this project will provide an excellent training in modern organic synthesis for the post-doctoral associate who will carry out the work. This will prepare this post-doctoral researcher for a career in academia or in a research or development laboratory in the fine chemicals industry. The pharmaceuticals industry in particular depends on medicinal chemists to design, discover and develop new pharmaceuticals, and very often seeks to recruit experienced synthetic organic chemists for this role. This project will provide an excellent education in this respect. The downstream impact of the training received by the post-doctoral researcher could therefore be very significant indeed.