Asymmetric Synthesis of Antitumor Agents

抗肿瘤药物的不对称合成

• 批准号: 6737525
• 负责人: JAMES S. PANEK
• 金额: $ 32.34万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-13 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737525
• 关键词: antineoplastic antibiotics; biological products; carbene; drug design /synthesis /production; heterocyclic compounds; phosphatase inhibitor; silanes; stereochemistry; stereoisomer

This research proposal reflects our interest in the development of new reaction processes and reagents in the areas of asymmetric catalysis and acyclic stereocontrol. The objectives that we intend to pursue will focus on the development and application of chiral silane reagents, although intensive activity in methodology development is outside the scope of this program. A new direction to be pursued during the budget period of this proposal will focus on the improvement of a existing reaction methodology concerning catalytic asymmetric carbene insertions into heteroatom-hydrogen bonds. We will also continue the development of double stereodifferentiating reactions and applications to the synthesis of anti-tumor antibiotics derived from terrestrial sources as well as marine sources. We intend to continue our efforts aimed at the completion of the asymmetric synthesis of herbimycin A, gledanamycin, and reblastatin. It is our objective to synthesize cyclotrienin and analogs. Cytotrienin A will be evaluated for its effect on the mitogene- activated protein kinase pathway using Saccharomyces cerevisiae as a model organism and genome-wide transcription polling techniques. It is our continuing objective to complete the asymmetric synthesis of ulapualide A, and confirm its stereochemical assignment. It is our continuing aim to identify and develop chiral metal catalysts for the catalyzed asymmetric intermolecular carene insertion reactions into heteroatom-hydrogen (cf Si-H and Sn-H) bonds. Although an in-depth mechanistic evaluation is outside the scope of this program, it is our short term objective to develop a number of useful synthetic transforms using this methodology, which include new approach to the synthesis of new chiral allylic silanes and stannanes.

这项研究计划反映了我们在不对称催化和非环立体控制领域开发新的反应过程和试剂的兴趣。我们打算追求的目标将集中在手性硅烷试剂的开发和应用上，尽管方法开发的密集活动不在本计划的范围之内。在本提案的预算期内将追求的一个新方向将集中于改进有关催化不对称碳插入杂原子-氢键的现有反应方法。我们还将继续发展双立体分化反应及其在陆源和海洋来源的抗肿瘤抗生素合成中的应用。我们打算继续努力，以完成herbyycin A， gledanamycin和reblastatin的不对称合成。我们的目的是合成环三联蛋白及其类似物。我们将利用酿酒酵母作为模式生物和全基因组转录轮询技术来评估细胞三烯蛋白A对有丝分裂基因激活的蛋白激酶途径的影响。完成乌拉普瓦利德A的不对称合成，并确定其立体化学定位是我们的持续目标。我们的目标是寻找和开发手性金属催化剂，用于催化不对称分子间插入反应形成杂原子-氢（如Si-H和Sn-H）键。虽然深入的机理评估超出了本计划的范围，但我们的短期目标是利用该方法开发一些有用的合成转化，其中包括合成新的手性烯丙基硅烷和锡烷的新方法。