Novel Approaches to Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

• 批准号: 7120581
• 负责人: BARRY M TROST
• 金额: $ 36.14万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120581
• 关键词: alkenes; alkylation; alkynes; antineoplastics; antiviral agents; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; glycosylation; macrolide antibiotics; molybdenum; nucleoside analog; palladium; ruthenium; sesquiterpenes; staurosporine; stereochemistry

The therapeutic importance of antitumor antiviral agents requires a continued effort to develop new methodology 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 unprecedented strategies for creating such molecular architectures. Asymmetric allylic akylation involving palladium and epoxides or related cyclic carbonates may provide a simple strategy to form a building block directed toward mitomycin - type structures. Inducing asymmetry at a prochiral nucleophile represents one of the most challenging tasks ever for chiral recognition in a catalytic asymmetric event. Preliminary successes stimulates its exploration. The breadth of applications is huge - ranging from alkaloids like the clinically important vinca alkaloids to macrocycles like peloruside A. A novel version combines asymmetric induction of a pronucleophile with a new class of pro-electrophiles, allenes, to create an extremely short synthesis of unusual amide types such as spirotyprostatin. A series of tandem stereospecific processes initiated by the asymmetric allylic alkylation invoking cyclic diketones creates a conceptually unprecedented approach to novel terpenes like terpestacin. New Ru catalyzed reactions being invented will be tested and explored in the synthesis of diverse polyketides like the laulimalides and pelorusides. A totally new concept for simple polyfunctional ring construction by atom economic additions is visualized via Ru catalyzed cycloisomerization or water addition to suitable diynes. Numerous targets emerge with the most exciting. In a number of projects, totally unprecedented selectivities in hdyrosilylation helps simplify the synthetic design including the mitomycin mimic and ptsloruside A. A direct asymmetric aldol protocol provides access to numerous structural types represented by leustroducsin, peloruside A, and apicularen A. By expediting access to very diverse arrays of structural types, the best opportunities to discover new therapeutic agents arise.

抗肿瘤抗病毒药物的治疗重要性需要不断努力开发新的方法来定义更好的合成策略。该项目选择已知具有此类生物活性的化合物类别作为目标，开发新的化学原理，这些原理可能会演变成创造此类分子架构的前所未有的策略。涉及钯和环氧化物或相关环状碳酸酯的不对称烯丙基烷基化可以提供形成针对丝裂霉素型结构的构件的简单策略。诱导前手性亲核试剂的不对称性是催化不对称反应中手性识别最具挑战性的任务之一。初步的成功刺激了它的探索。应用的广度是巨大的-从生物碱如临床上重要的长春花生物碱到大环化合物如Peloruside A。一个新的版本结合了不对称诱导的亲核试剂与一类新的亲电试剂，联烯，创造一个非常短的合成不寻常的酰胺类型，如spirotyprostatin。一系列的串联立体定向过程引发的不对称烯丙基烷基化调用环状二酮创造了一个概念上前所未有的方法，以新的萜烯，如terpestacin。正在发明的新的钌催化反应将在合成不同的聚酮化合物如laulimalides和pelorusides中进行测试和探索。一个全新的概念，简单的多官能环建设的原子经济加成是可视化通过钌催化环异构化或水加成到合适的二炔。众多的目标出现了最令人兴奋的。在许多项目中，氢化硅烷化的完全前所未有的选择性有助于简化合成设计，包括丝裂霉素模拟物和ptsloruside A。直接不对称羟醛缩合方案提供了对以leustroducsin、peloruside A和apicularen A为代表的许多结构类型的访问。通过加速获得非常多样化的结构类型阵列，发现新治疗剂的最佳机会出现了。