NOVEL APPROACHES TO ANTITUMOR AND ANTIVIRAL AGENTS

抗肿瘤和抗病毒药物的新方法

• 批准号: 6180470
• 负责人: BARRY M TROST
• 金额: $ 28.85万
• 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/6180470
• 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 继续努力确定更好的合成策略。 选择 这类化合物以其生物活性而闻名， 该项目开发了新的化学原理，可能会演变成 创造这种分子结构的前所未有的策略。 利用手性Pd催化剂的不对称诱导提供了许多 实现不对称诱导的方法。 区分对映异构体 离去基团为核苷的新范例开辟了前景 由呋喃合成。 探索多种结构类型 其中所述杂环碱基、C-5侧链以及2-和3-碳原子的杂环碱基是 取代基可以变化，将进行检查，以建立有效性 这个新概念的灵活性。 的实用不对称合成 诸如AZT、DDI、DDDC、司他夫定、法扎拉宾、 showdomycin，cadequomycin，曲马新，sinefugin，多抗霉素，和 可能导致金霉素。 一种新的方法来影响分子 对相关抗肿瘤药物星形孢菌素的认可 和K252 a可以简单地合成这些化合物。 考虑到前手性烯丙基酯络合的概念， 提供了一种合成吲哚生物碱的策略， 抗病毒剂eudistomin E. 基于亲核类型 可以用于这样的综合，提出了一个新的推力，形成 环肽具有不寻常的氨基酸，以利用 大环化的效率如抗肿瘤剂所示， 所述glidobactins。 从以下概念衍生的新反应族的创建： 金属催化的分子间和分子内加成反应导致 新的战略眼光。 基于Ru催化的烯型 反应，逆合成分析了一些日益增长的一类 高活性试剂，乙酸配基，可以以高活性的方式被引入。 收敛、高效和简单的方式。 一个环的环异构化 使用Pd或Ru的烯型提供了一种通常的方法， 发现了以saponaceolides为代表的结构。 延长 烷基化烯炔环化的概念为一个非常重要的 表鬼臼毒素短合成 机械方面的考虑导致 到另一个维度的创造--一个烯炔复分解-- 为新型桥双环抗肿瘤药物的开发创造了机会， 代表性的是玫瑰素，更重要的是紫杉醇。 一种新型 涉及末端炔的金属催化加成导致 用于产生核苷的不同范例，如Griseolic所示 acids. 炔二烯类抗肿瘤药物的高灵敏度功能 例如，Tricholomenym A和B成为这些细菌的天然靶标， 方法论 合成方法的真正勇气无法判断 直到在“战场”--一个复杂的合成目标上进行检验。 抗肿瘤和抗病毒药物带来的挑战的多样性 代理代表了对其使用的非常有意义的测试。 同样 重要的，新的途径来改变围绕这些核心的结构， 建立构效关系，以创造更好的 治疗剂变得可用。