Novel Approaches to Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

基本信息

批准号：
7488772
负责人：
BARRY M TROST
金额：
$ 34.11万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/7488772
关键词：
1,3-Butadiene 3-hydroxybutanal Alcohols Alkaloids Alkenes Alkylation Alkynes Amides Amines Antiviral Agents Architecture Attention Biological Carbon Carbonates Chemicals Claisen rearrangement Class Complex Coupling Development Diels Alder reaction Dimerization Distant Economics Educational process of instructing Epoxy Compounds Equilibrium Event FR 900482 Facility Construction Funding Category Family Hydrolysis Lactams Lanthanoid Series Elements Lead Metals Methodology Methods Mitomycin Mitomycins Molecular Numbers Object Attachment Palladium Pattern Process Proline Protocols documentation Pyrans Range Reaction Reagent Role Route Series Side Stretching Structure System Terpenes Testing Therapeutic Therapeutic Agents Time Translating Translations Vinca Alkaloids Vindoline Water Zinc apicularen A base carbonyl group catalyst concept design diene diketone enantiomer enolate epoxyquinol A functional group hydroxyl group insight laulimalide monomer novel novel strategies novel therapeutics peloruside A propadiene success terpestacin

项目摘要

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，这些原理可能演变成创建此类分子结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一种简单的策略来形成针对丝裂霉素型结构的构建块。在前手性亲核试剂处诱导不对称性是催化不对称事件中手性识别中最具挑战性的任务之一。初步的成功激发了它的探索。应用范围非常广泛 - 从生物碱（如临床上重要的长春花生物碱）到大环化合物（如 pelosuside A）。一种新颖的版本将亲核试剂的不对称诱导与一类新的亲电子试剂（丙二烯）相结合，以创建非常短的合成酰胺类，例如螺酰前列腺素。由调用环二酮的不对称烯丙基烷基化引发的一系列串联立体定向过程为新型萜烯（如terpestacin）创造了概念上前所未有的方法。正在发明的新型钌催化反应将在多种聚酮化合物（如月桂马内酯和罗糖苷）的合成中进行测试和探索。通过Ru催化的环异构化或水加成到合适的二炔中，通过原子经济加成来构建简单的多官能环的全新概念被可视化。许多目标出现，其中最令人兴奋的。在许多项目中，氢化硅烷化中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。直接不对称羟醛协议提供了以 leustroducsin、peloruside A 和 apularen A 为代表的多种结构类型。由于结构类型多种多样，发现新治疗剂的最佳机会出现了。