SYNTHESIS OF SPONGISTATIN ANTITUMOR AGENTS

该研究计划的主要目标是开发一种实用的合成方法来合成spongipyran 1（1），这是一个新的结构独特的双螺酮缩大环内酯家族中最有效的成员，具有非凡的抗肿瘤活性。 三个研究小组已经分离出了海绵吡喃家族的成员，他们分别将其命名为spongistatins 1 - 9、cinachyrolide A和altohyrtins A、B和C。spongistatin似乎是迄今为止发现的最有效的癌细胞生长抑制剂。未来四年的具体目标是：（A）竞争我们的第一代合成海绵抑素2（2）;（B）设计一种高效的第二代合成策略，能够提供至少1克的海绵抑素1（1），在适当的情况下利用我们实验室开发的新方法;和（C）制备精心设计的海绵抑素类似物文库以阐明这类重要的抗肿瘤剂的药效团。 在后一个方面，我们与亚利桑那州立大学癌症研究所所长Pettit教授有着长期的合作，他不仅同意分析我们设计的类似物和先进的合成中间体，而且还同意探索最有希望的抗肿瘤候选物的作用模式，以进行可能的进一步开发。 除了预期的制药影响外，这项事业的成功将构成复杂分子合成的一项重大成就。 此外，该计划将作为研究生和博士后学生在学术界和制药行业的职业生涯的优秀培训。结合海绵抑素1（1）的拟议合成，我们将（D）研究甲硅烷基二噻烷与氮杂环丙烷和其他潜在亲电试剂的多组分关键偶联。 这是基于我们在复杂结构组装中的二噻烷偶联方面的丰富经验。最后，我们将（E）开发一种新的双功能试剂，用于利用布朗不对称烯丙基硼化作用获得各种高烯丙基结构单元。 该方法有望成为有效组装复杂多元醇片段以及取代的吡喃环的有价值的协议，这两者在天然产物合成中起着重要作用。我们实验室的这一项目和相关项目的一个中心主题是（并将继续是）开发有效的合成策略，这些策略不是单一目标导向的，而是允许构建整个类别的天然产物。 我们认为，这一"统一的"综合战略"的理念将在本提案中得到充分体现。

The principal goal of this research program is to develop a practical synthetic approach to spongipyran 1 (1), the most potent member of a new family of architecturally unique bisspiroketal macrolides which possess extraordinary antitumor activities. Three research groups have isolated members of the spongipyran family which they designated the spongistatins 1-9, cinachyrolide A, and the altohyrtins A, B and C, respectively. The spongistatins appear to be the most potent inhibitors of cancer cell growth discovered to date. The specific aims for the next four year period are: (A) to compete our first-generation synthesis of spongistatin 2 (2); (B) to devise a highly efficient second-generation synthetic strategy capable of delivering a minimum of one gram of spongistatin 1(1), exploiting where appropriate new methodology developed in our laboratory; and (C) to prepare a carefully designed library of spongistatin analogs to elucidate the pharmacophore of this important class of antitumor agents. Towards the latter end, we have a long standing collaboration with Professor Pettit, Director of the Cancer Research Institute, Arizona State University, who has agreed not only to assay our designed analogs and advanced synthetic intermediates, but also to explore the mode of action of the most promising antitumor candidates, for possible further development. Apart from the anticipated pharmaceutical impact, success in this venture would constitute a major achievement for complex molecule synthesis in general. In addition, this program will serve as excellent training for graduate and postdoctoral students for careers in both academia and the pharmaceutical industry. In conjunction with the proposed synthesis of spongistatin 1 (1), we will (D) investigate our multicomponent linchpin coupling of silyl dithianes with aziridines and other potential electrophiles. This builds upon our extensive experience with dithiane coupling in the assembly of complex structures. Finally, we will (E) develop a new bifunctional reagent for accessing a variety of homoallylic building blocks taking advantage of the Brown asymmetric allylboration. This method holds promise as a valuable protocol for efficient assembly of complex polyol fragments, as well as substituted pyran rings, both of which play an important role in natural product synthesis. A central theme of this and related programs in our laboratory is (and will continue to be) the development of effective synthetic strategies that are not single-target oriented, but instead will permit construction of entire classes of natural products. We believe that this philosophy of "unified" synthetic strategies" will be amply demonstrated in this proposal.