Details of Grant 

EPSRC Reference:	GR/S87119/01
Title:	Completion of Synthesis of Bryostatins
Principal Investigator:	Thomas, Professor EJ
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Chemistry
Organisation:	University of Manchester, The
Scheme:	Standard Research (Pre-FEC)
Starts:	23 September 2004	Ends:	22 July 2008	Value (£):	259,763
EPSRC Research Topic Classifications:	Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:	Pharmaceuticals and Biotechnology
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Summary on Grant Application Form
The bryostatins are a group of about twenty macrocyclic compounds isolated from marine animals which show potent anticancer activity. Indeed they are presently being evaluated in man for the treatment of various kinds of cancer. Until very recently, the supply of bryostatins from natural sources was very limited and severely restricted their proper biological evaluation. However this situation has recently changed with the introduction of improved aquaculture techniques which it is hoped will provide 100 g quantifies of the bryostatins for clinical evaluation. Nevertheless, there remains an urgent need for synthetic chemistry to provide access to a wider range of bryostatins for full structure activity studies.To date, many approaches to the synthesis of bryostatins have been reported in the literature but, because of the complexity and inaccessability of these compounds, only three total syntheses of natural bryostatins have been completed. These syntheses constitute major achievements in themselves but are so complex that they have provided only very small amounts of material and have not significantly improved the availablity of bryostatins for biological studies although they have contributed greatly to our understanding of organic synthesis and the development of new methods.It is proposed to develop a synthetic approach to the bryostatins which should provide new analogues for biological evaluation. It is intended to prepare gram quantities of substantive fragments which when combined with modified fragments will lead to both natural products and analogues. To date syntheses have been completed of advanced precursors on the10 - 20 gram scale. It remains to find procedures for the efficient assembly of these fragments to access the bryostatin nucleus. Once our approach has been validated by the completion of a synthesis of a natural bryostatin, bryostatin 10, analogues will be prepared which contain the natural C(1)-C(16) fragment but unnatural C(17}C(27) fragments for biological testing. This work will complement that of Wender who, by maintaining the latter fragment but with various former fragments, has prepared analogues with biological activities equal to, and in some cases better than, the natural material.This is an ambitious programme of research which will take many years. The immediate objectives are to find effective procedures for the assembly of the bryostatin nucleus and complete a synthesis of a natural product by a route which should enable analogues to be prepared on the 50 -100 mg scale for biological evaluation from readily accessible intermediates.
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