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.

开发新的和新颖的合成方法对四个不同的家庭 提出了抗肿瘤剂的。 这样，系统的结构变化 可以执行这些具有已知活性的化合物中的类别 结构活动关系。 Catharanthine，一种生物碱之一 对于文素和长春新碱的半合成方法，将使用 过渡金属化学。 通过Diels-Alder的新型不对称合成 反应也被调用。 第二部分涉及抗血性虹膜的 阿拉曼丁。 该策略开发了一种新的方法来烷基化， 通过刚性bicyclo（3.3.0）辛烷值和新颖的立体化学开发 调节碳氧化水平的方法。 第三部分涉及 柱状霉素A的良性aglycone A的毒性比其他成员的毒性小 这个家庭，例如daunomycin和adrimycin。 该方法以小说为特色 创建受保护的酚环的方法，使用由硫控制的二烯 替代以及一个不寻常的新保护小组的发展。 扩大 考虑到阿克拉类霉素A的良性。 第四部分处理 Verrucarin A是最有效的细胞抑制剂家族的成员 已知。 它是使用secoalalyation的概念和修改的概念 通过有机硫的中间体氧化水平。 一个新颖的创作 提出了通过Claisen重排的Bicyclo（3.3.1）滑石系统。