NOVEL SYNTHETIC APPROACHES TO ANTITUMOR COMPOUNDS

抗肿瘤化合物的新合成方法

• 批准号: 3282392
• 负责人: BARRY M TROST
• 金额: $ 24.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3282392
• 关键词: Diels Alder reaction; alkylation; antileukemic agent; antineoplastics; chemical structure function; daunorubicin; doxorubicin; drug design /synthesis /production; stereochemistry

The development of new and novel synthetic approaches to four different families of antitumor agents is proposed. In this way, systematic structural variation of these classes of compounds with known activity can be performed to develop structure-activity relationships. Catharanthine, one of the alkaloids for a semisynthetic approach to vinblastine and vincristine, will be approached using transition metal chemistry. A novel asymmetric synthesis via a Diels-Alder reaction is also invoked. The second part deals with the antileukemic iridoid allamandin. The strategy develops a new approach to secoalkylation, the development of stereochemistry via the rigid bicyclo(3.3.0)octane, and novel ways to adjust oxidation level of carbon. The third part deals with the aglycone of pillaromycin A which is known to be less toxic than other members of this family such as daunomycin and adriamycin. The approach features a novel way to create a protected phenolic ring, the use of dienes controlled by sulfur substitution, and the development of an unusual new protecting group. Extension to the aglycone of aclacinomycin A is considered. The fourth part deals with verrucarin A which is a member of the family of most potent cytostatic agents known. It is approached using the concept of secoalkylation and modification of oxidation level via organosulfur intermediates. A novel creation of the bicyclo(3.3.1)oxanonane system via a Claisen rearrangement is proposed.

四个不同家族的新型合成方法的开发 提出了抗肿瘤剂。 这样，系统性的结构变异 可以对这些具有已知活性的化合物进行开发 结构-活性关系。 长春碱，生物碱之一 长春花碱和长春新碱的半合成方法，将使用 过渡金属化学。 通过 Diels-Alder 进行的新型不对称合成 反应也被调用。 第二部分涉及抗白血病环烯醚萜 阿拉曼丁。 该策略开发了一种新的环烷基化方法， 通过刚性双环（3.3.0）辛烷开发立体化学，并新颖 调节碳氧化水平的方法 第三部分涉及 柱霉素 A 的苷元，已知其毒性低于其他成员 这个家族如道诺霉素和阿霉素。 该方法具有新颖性 创建受保护的酚环的方法，使用受硫控制的二烯 取代，以及一种不寻常的新保护基团的开发。 扩大 考虑到阿克拉霉素A的糖苷配基。 第四部分涉及 verrucarin A 是最有效的细胞抑制剂家族的成员 已知。 它是利用环烷基化和修饰的概念来实现的 通过有机硫中间体的氧化水平。 的新颖创作 提出了通过克莱森重排的双环(3.3.1)氧杂壬烷系统。