Novel Approaches to Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

• 批准号: 6330866
• 负责人: BARRY M TROST
• 金额: $ 38.06万
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330866
• 关键词: alkenes; alkylation; alkynes; antineoplastics; antiviral agents; drug design /synthesis /production; glycosylation; macrolide antibiotics; molybdenum; nucleoside analog; palladium; sesquiterpenes; staurosporine; stereochemistry

The therapeutic importance of antitumor and antiviral agents requires a continued effort to define better synthetic strategies. Choosing classes of compounds known for this type of biological activity as targets, this project develops new chemical principles that may evolve into unprecendented strategies for creating such molecular architectures. Asymmetric allylic alkylation with catalysts derived from palladium and molybdenum requires a rethinking of synthetic strategy, but also brings unprecedented potential power. Developing new paradigms for making nucleosides free of a dependence on carbohydrate starting materials has the real prospect of simplifying and streamlining syntheses, providing either enantiomeric series with equal ease, and allowing access to unusual analogues. This chemistry can make carbocyclic analogues as easily available as the furanose ones. A novel way to effect glycosylations may provide the first diastereocontrolled systems represented by staurosporine, K252a, and indocarbazostatin. Using tandem palladium catalyzed processes, the first one of which is an asymmetric allylic alkylation provides an entry to such diverse structures as the furaquinocins, macrocycles like cochleamycin, and glycosidase inhibitors by a new class, the broussonetines which may help to define protein targets as well as lead to new therapies. Understanding the phenomena of tumor promoting agents like phorbol will derive from having access to agents like karamatsuic acid which inhibits such actions. Creation of a family of new reactions derived from the concept of metal catalyzed inter-and intramolecular addition reactions leads to several new strategic insights. Based upon a Ru catalyzed ene type reaction, retrosynthetic analysis of a number of a growing class of highly active agents, the amphidinolides, may be broached in a highly convergent, efficient and simple fashion. Wedding the alkyne-alkene coupling to a palladium catalyzed asymmetric allylic alkylation opens the opportunity to the novel 14-membered macrolide, callipeltoside, which inhibits proliferation of human non-small lung carcinoma as well as protect cells infected with the HIV virus. Modifications of the palladium catalyst shifts the alkyne-alkene ene-type reaction into a novel metathesis process. This new chemistry provides access to bridged macrobicyclics as illustrated by neoliacinic acid, a new type of germacranolide-sesquiterpene exhibiting good antitumor activity. By accessing a very diverse range of structural types, the best opportunities to discover new therapeutic agents arise.

抗肿瘤和抗病毒药物的治疗重要性需要持续努力，以确定更好的合成策略。 该项目选择以这种生物活性为目标的化合物类别，开发新的化学原理，这些原理可能会演变成创造这种分子结构的前所未有的策略。 钯钼催化剂的不对称烯丙基烷基化反应需要重新思考合成策略，但也带来了前所未有的潜在动力。 开发使核苷不依赖于碳水化合物起始材料的新范例具有简化和流线化合成的真实的前景，以同样的容易度提供任一对映体系列，并允许获得不寻常的类似物。 这种化学方法可以使碳环类似物像呋喃糖一样容易获得。 一种实现糖基化的新方法可以提供以星形孢菌素、K252 a和indocarbazostatin为代表的第一个非对映体控制系统。 使用串联钯催化的方法，其中第一个是不对称烯丙基烷基化，提供了一个进入到这样的不同结构的呋喹菌素，大环如耳蜗霉素，和糖苷酶抑制剂的一个新的类别，broussonetines，这可能有助于确定蛋白质的目标，以及导致新的治疗。 了解像佛波醇这样的肿瘤促进剂的现象将来自于获得像karamatsuic酸这样的抑制这种作用的药物。从金属催化的分子间和分子内加成反应的概念出发，建立了一系列新的反应，从而产生了一些新的战略见解。 基于钌催化的烯型反应，逆合成分析的一个日益增长的一类高活性剂，amphidinolides，可以在一个高度收敛，高效和简单的方式broached。将炔-烯烃偶联与钯催化的不对称烯丙基烷基化结合为新型14元大环内酯类化合物callipeltoside提供了机会，其抑制人非小细胞肺癌的增殖并保护被HIV病毒感染的细胞。 钯催化剂的改性将炔-烯-烯型反应转变为新的复分解过程。 这种新的化学方法提供了获得桥连大双环的途径，如新柳杉酸所示，新柳杉酸是一种新型的大根香叶内酯-倍半萜，具有良好的抗肿瘤活性。 通过获得非常多样化的结构类型，发现新治疗药物的最佳机会出现了。