Synthesis of Antitumor Natural Products

抗肿瘤天然产物的合成

• 批准号: 6621041
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 59.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-03-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621041
• 关键词: antineoplastics; asparagine; chemical synthesis; drug design /synthesis /production; enzyme inhibitors; glycoproteins; heat shock proteins; neurotrophic factors; phospholipase A2; synthetic tumor antigen

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.

我们实验室的使命是作为一个资源，为有机合成的进步，针对相对复杂的目标。在我们追求这些目标的过程中，我们开发的化学物质被用于解决对人类健康有影响的多学科问题。 我们实验室解决这类问题的能力，来自于它所展示的吸引化学家的能力，这些化学家已经精通或渴望精通处理相当复杂的目标系统的能力。 我们的问题选择过程集中在天然产物的目标，进行相当大的生物学兴趣，并反映了我们的信心，适当的想象力和毅力，所需的系统可以组装的数量适合研究其生物学分支。 我们不仅考虑传统的植物化学，微生物和珊瑚的代谢产物，但也复杂的细胞表面糖缀合物（特别是糖肽和糖蛋白结构）对应于肿瘤相关抗原。我们的CA 28824 24-28项目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方面做出巨大努力（项目i）。由于用完全合成的基于单一碳水化合物的抗原进行的I期研究产生了相当有利的血清学结果，因此在追求这些问题方面存在特别的紧迫性。 我们认为，我们现在有可能通过完全化学合成获得糖蛋白。这一目标将涉及将N-（天冬酰胺）连接糖肽合成技术与蛋白质连接技术合并（项目ii）。 我们还处理12，13-desoxyepothilone领域的重要问题。 我们的目标是利用全合成来产生非前药的、水溶性的埃博霉素。我们将借鉴我们最近完成的12，13-脱氧坡噻酮F的全合成（项目iii）。 此外，我们将寻求完成几个有趣的天然产物的全合成。这些包括pinnaic acid（一种PLA 2抑制剂;项目iv）、根赤霉素（一种Hsp-90抑制剂;项目v）、merrilactone A（一种非肽类小分子神经营养因子;项目vi）、螺毒素（一种DNA裂解剂;项目vii）和TMC-95 A（靶向蛋白体蛋白水解;项目viii）。 总之，我们的计划将在可行性的周边有机合成的问题为特色。 这些努力将与重要的生物学问题，特别是抗癌领域的问题联系起来。