Convergent synthesis of Bryostatins

多年来，从天然来源(例如植物)中分离出来的化合物为药物和药物的发现提供了非常重要的线索。最近，从海洋微生物中分离出了许多非常复杂的化合物，并发现它们具有抗癌活性。其中一类化合物是苔藓他汀类化合物。它们显示出强大的生物活性，并正在世界各地的许多临床试验中进行临床应用测试。问题是，获得苔藓类药物非常困难。水产养殖技术每年提供几百克的一种苔藓植物抑素，但这种供应不能满足需求，尤其是没有提供足够的材料来进行研究结构对生物活性的影响所需的化学修饰。到目前为止，已经报道了三种苔藓他汀类化合物的合成，其中两种来自美国，一种来自日本。这些都是现代和复杂的化学合成的杰出例子，但由于它们的长度，不能为生物研究提供大量的苔藓他汀类药物或类似物。它的目的是开发一种较短的苔藓类化合物的合成，为研究结构对生物活性的影响提供合成类似物的途径。最初，将准备一种自然产生的Bryostatin来开发该方法，但这将为类似物的制备开辟道路。长期目标是制备一种生物活性更高、毒性更低的更简单的类似物，尽管超出了本申请的范围，但这是一项非常雄心勃勃的计划，在这一层面上很难进行合成有机化学。本申请旨在资助一名经验丰富的研究人员在这一领域继续学习12个月。在此期间，我们打算最终确定我们的合成策略，准备与Bryostatin接近的类似物，并有望制备一种天然的Bryostatin，从而确立我们方法的可行性。

Compounds isolated from natural sources, for example plants, have provided very important leads over the years for the discovery of drugs and pharmaceuticals. Recently, many very complicated compounds have been isolated from microorganisms in the sea and found to possess anti-cancer activity. One such group of compounds are the bryostatins. These display potent biological activity and are being tested for clinical use in many trials worldwide. The problem is that access to the bryostatins is very difficult. Aquaculture techniques are providing a few hundred grammes a year of one of the bryostatins, but this supply is not meeting demand and, in particular, is not providing enough material for the chemical modifications necessary for a study of the influence of structure on biological activity. To date, three syntheses of bryostatins have been reported, two from the USA and one from Japan. These are outstanding examples of modern and sophisticated chemical synthesis but because of their length cannot contribute significantly to the supply of bryostatins or analogues for biological studies.It is intended to develop a shorter synthesis of bryostatins which will provide access to synthetic analogues for studies of the effect of structure on biological activity. Initially a naturally occurring bryostatin will be prepared to develop the methodology but this should open the way for the preparation of analogues. The longer term objective, albeit outside the scope of this application, is to prepare a simpler analogue with improved biological activity and reduced toxicityHowever, this is a very ambitious programme and synthetic organic chemistry at this level is very difficult to carry out. The present application is for support for an experienced research worker to continue our studies in this area for twelve months. During this time it is intended to finalise our synthetic strategy, to prepare close analogues of the bryostatins, and hopefully prepare a natural bryostatin, so establishing the viability of our approach.