NOVEL APPROACHES TO ANTITUMOR AND ANTIVIRAL AGENTS

抗肿瘤和抗病毒药物的新方法

• 批准号: 2021986
• 负责人: BARRY M TROST
• 金额: $ 28.03万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2021986
• 关键词: alkaloids; alkynes; antineoplastics; antiviral agents; carbopolycyclic compound; catalyst; chemical reaction; chemical structure function; cyclic peptides; cyclization; drug design /synthesis /production; methylation; mitomycins; nucleoside analog; palladium; podophyllin; ruthenium; stereochemistry; terpenes

The therapeutic importance of antitumor and antiviral agents requires a continued effort to define better synthetic strategies. Choosing classes of compounds known for their biological activity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Asymmetric induction utilizing a chiral Pd catalyst offers a number of ways to effect asymmetric induction. Differentiating enantiotopic leaving groups opens the prospect of a new paradigm for nucleoside synthesis from furan. Exploration of a variety of structural types wherein the heterocyclic base, the C-5 side chain, and the 2- and 3- substituents can be varied will be examined to establish the validity and flexibility of this new concept. Practical asymmetric syntheses of such diverse systems as AZT, DDI, DDDC, stavudine, fazarabine, showdomycin, cadequomycin, queuosine, sinefugin, polyoxins, and chryscandin may result. A novel way to effect the molecular recognition required for the related antitumor agents staurosporine and K252a can result in simple syntheses of these compounds. Considering the concept of complexation of prochiral allyl esters can provide a strategy for the synthesis of indole alkaloids represented by the antiviral agent eudistomin E. Building upon the type to nuclephile that can be used in such a synthesis, suggests a new thrust for forming cyclic peptides possessing unusual amino acids to capitalize on the efficiency of macrocyclizations as illustrated by the antitumor agents, the glidobactins. 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 acetogenins, may be broached in a highly convergent, efficient and simple fashion. A cycloisomerization of an ene type using either Pd or Ru provides an approach to a commonly found structure as represented by the saponaceolides. Extension of the concept to an alkylative enyne cyclization sets the stage for a very short synthesis of epipodophyllotoxin. Mechanistic considerations led to the creation of another dimension-an enyne metathesis-which creates opportunities to the novel bridge bicyclic antitumor agents represented by roseophilin and, more significantly, taxol. A new type of metal catalyzed additions involving terminal alkynes leads to a different paradigm for creation of nucleosides as illustrated by griseolic acids. The highly sensitive functionality of ynediene antitumor agents like tricholomenym A and B become natural targets for such methodology. The true mettle of synthetic methods cannot be judged until it is tested in "the field of battle"-a complex synthesis target. The diversity of the challenges posed by the antitumor and antiviral agents represent highly meaningful tests of their use. Equally important, new avenues to vary structure around these cores in order to establish structure-activity relationships with the aim to create better therapeutic agents become available.

抗肿瘤和抗病毒剂的治疗重要性需要 继续努力定义更好的合成策略。 选择 以其生物活性为靶标而闻名的化合物类别 项目制定了可能发展为 创建这种分子体系结构的前所未有的策略。 使用手性PD催化剂的不对称诱导提供了许多 影响不对称诱导的方法。 区分对映体 离开组打开了新的核苷范式的前景 弗兰的合成。 探索各种结构类型 其中杂环底座，C-5侧链以及2和3- 可以检查取代基以建立有效性 和这个新概念的灵活性。 实用的不对称合成 诸如AZT，DDI，DDDC，Stavudine，Fazarabine等多样化系统 showdomycin，cadequomycin，queuosine，sinefugin，多氧蛋白和 可能会导致chryscandin。 实现分子的新方法 相关抗肿瘤剂Staurosporine所需的识别 和K252A可以导致这些化合物的简单合成。 考虑到学术烯丙烯酯的复合概念可以 提供了合成吲哚生物碱的策略 抗病毒剂Eudistomin E.建立在核球类型的基础上 可以在这种综合中使用，这提示了形成的新推力 具有异常氨基酸的环状肽可大写 抗肿瘤剂所示的大环化效率， Glidobactins。 从概念中得出的新反应家族的创造 金属催化的分子间和分子内添加反应导致 几个新的战略见解。 基于RU催化的ENE类型 反应，多个生长类别的反思分析 高活性剂，乙酰蛋白，可以在高度的 收敛，高效和简单的时尚。 一个环化学 使用PD或RU的ENE类型提供了一种通常的方法 发现的结构如saponaceolides所示。 扩展 烷基化Enyne环化的概念为一个非常 附属植物毒素的短合成。 机械考虑LED 创建另一个维度 - 一个恩尼的元矫正 - 为新颖的桥梁双环抗肿瘤代理创造机会 由玫瑰油和更重要的是紫杉醇代表。 一种新类型 涉及末端炔烃的金属催化添加剂导致 如谷物所示，用于创建核苷的不同范式 酸。 Ynediene抗肿瘤剂的高度敏感功能 像Tricholomenym A和B一样成为这种自然目标 方法论。 真正的合成方法的真正元素无法判断 直到在“战场”中进行测试 - 一个复杂的合成目标。 抗肿瘤和抗病毒带来的挑战的多样性 代理代表了对其使用的高度有意义的测试。 同样 重要的是，按顺序围绕这些核心变化的新途径 建立结构性关系，以创造更好的目的 治疗剂可用。