Synthesis of Antitumor Natural Products

我们实验室的任务是作为一个资源，促进针对相对复杂的目标的有机合成。在我们追求这些目标的同时，我们开发的化学被用于处理对人类健康有影响的多学科问题。我们实验室在问题中发挥作用的能力，如果发生在这种情况下，是因为它有能力吸引那些已经精通或急于精通于获得处理相当复杂的目标系统的能力的化学家。我们的问题选择过程将重点放在具有相当大生物兴趣的天然产品目标上，并反映出我们的信心，即只要有适当的想象力和毅力，所需系统就可以组装成适合研究其生物分支的数量。我们不仅考虑了传统的植物化学、微生物和珊瑚代谢物，还考虑了与肿瘤相关抗原相对应的复杂细胞表面糖偶联物(特别是糖肽和糖蛋白结构)。我们的CA28824 24-28计划将在形成和优化第二代和第三代基于碳水化合物的抗肿瘤疫苗(项目I)方面做出巨大努力。由于用完全合成的单一碳水化合物为基础的抗原进行的第一阶段研究产生了相当好的血清学结果，因此特别迫切地追求这些问题。我们认为，现在我们可以通过充分的化学合成来获得糖蛋白。这一目标将涉及将N-(天冬酰胺)连接的糖肽合成技术与蛋白质连接技术(项目II)相结合。我们还处理12，13-脱氧丙硫酮领域的重要问题。我们的目标是使用全合成来合成非前药、水溶性的埃普罗酮。我们将利用我们最近完成的12，13-脱氧苯硫酮F的全合成(项目III)。此外，我们还将寻求完成几种有趣的天然产物的全合成。这些药物包括品尼酸(一种PLA2抑制剂；项目四)、自由基(一种热休克蛋白-90抑制剂；项目五)、美利内酯A(一种非肽类小分子神经营养因子；项目六)螺杆菌毒素(一种DNA裂解剂，项目七)和TMC-95A(针对蛋白酶体蛋白分解；项目八)。总而言之，我们计划的计划将在可行性范围内突出有机合成方面的问题。这些努力将与重大的生物关切问题联系在一起，特别是在抗癌领域。

The mission of our laboratory is to serve as a resource for the advancement of organic synthesis directed to relatively complex targets. As we pursue these goals, the chemistry we develop is brought to bear on multidisciplinary problems with implications for human health. The ability of our laboratory to function in problems if this sort arises from its demonstrated capacity to attract chemists who are already well versed or anxious to become well versed in gaining the capability to deal with goal systems of considerable complexity. Our problem selection process focuses on natural product targets which carry considerable biological interest, and reflects our confidence that with appropriate imagination and persistence, the desired systems can be assembled in amounts suitable for studying their biological ramifications. We consider not only traditional phytochemical, microbial and coral metabolites, but also complex cell surface glycoconjugates (particularly glycopeptides and glycoprotein constructs) corresponding to tumor associated antigens. Our program for CA28824 24-28 will involve a large effort in fashioning and optimizing second and third generation carbohydrate based antitumor vaccines (project i). There is a particular urgency in pursuing these matters since Phase I studies conducted with fully synthetic single carbohydrate based antigens produced quite favorable serological results. We feel that it is now possible for us to obtain a glycoprotein by full chemical synthesis. This goal will involve merging the technology of N-(asparagine) linked glycopeptide synthesis with protein ligation (project ii). We also deal with important issues in the 12,13-desoxyepothilone area. Our goal is to use total synthesis to generate non-prodrug, water soluble epothilones. We will be drawing on our recently completed total synthesis of 12, 13-desoxyepothilone F (project iii). In addition, we will be seeking to accomplish the total synthesis of several interesting of several interesting natural products. These include pinnaic acid (a PLA2 inhibitor; project iv), radicicol (an Hsp-90 inhibitor; project v), merrilactone A (a non peptidal small molecule neurotrophic factor; project vi) spiroxin (a DNA cleaving agent; project vii) and TMC-95A (which targets proteosomal proteolysis; project viii). In summary, our projected program will feature issues in organic synthesis at the perimeter of feasibility. These efforts will be linked to questions of significant biological concern, particularly in the anticancer field.