NOVEL APPROACHES TO ANTITUMOR AND ANTIVIRAL AGENTS

抗肿瘤和抗病毒药物的新方法

• 批准号: 2770926
• 负责人: BARRY M TROST
• 金额: $ 27.36万
• 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/2770926
• 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.

抗肿瘤和抗病毒药物的治疗重要性要求 持续努力定义更好的合成策略。 选择 以其生物活性而闻名的化合物类别作为目标，这 项目开发了新的化学原理，可能演变成 创建这种分子结构的前所未有的策略。 利用手性 Pd 催化剂的不对称感应提供了许多 影响不对称感应的方法。 区分对映体 离去基团开辟了核苷新范式的前景 由呋喃合成。 多种结构类型的探索 其中杂环碱基、C-5侧链、以及2-和3- 取代基可以变化，将进行检查以确定有效性 以及这个新概念的灵活性。 实用不对称合成 AZT、DDI、DDDC、司他夫定、法扎拉滨等多种系统， showdomycin、cadequomycin、queuosine、sinefugin、polyoxins 和 可能会产生chryscandin。 一种影响分子的新方法 相关抗肿瘤药物星形孢菌素所需的认可 K252a 和 K252a 可以实现这些化合物的简单合成。 考虑到前手性烯丙酯络合的概念可以 提供了以吲哚生物碱为代表的合成策略 抗病毒剂 eudistomin E. 基于亲核试剂类型 可以用于这种合成，提出了形成的新推动力 环肽具有不寻常的氨基酸，可利用 如抗肿瘤剂所示的大环化效率， 格列多菌素。 源自概念的一系列新反应的创建 金属催化的分子间和分子内加成反应导致 一些新的战略见解。 基于 Ru 催化烯类型 反应，对越来越多的类别进行逆合成分析 高活性药物，即乙酰丙酮，可以在高度 汇聚、高效、简约时尚。 环异构化 使用 Pd 或 Ru 的烯类型提供了一种常见的方法 发现了以皂苷为代表的结构。 延伸 烷基烯炔环化的概念为非常 表鬼臼毒素的简短合成。 机制考虑主导 创造另一个维度——烯炔复分解—— 为新型桥接双环抗肿瘤药物创造机会 以玫瑰亲红素和更重要的是紫杉醇为代表。 一种新类型 涉及末端炔烃的金属催化加成导致 产生核苷的不同范例，如 griseolic 所示 酸。 炔二烯抗肿瘤剂的高度敏感功能 像 tricholomenym A 和 B 成为此类的自然目标 方法论。 合成方法的真伪无法判断 直到在“战场”——复杂的合成目标上进行测试。 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 围绕这些核心改变结构的重要的新途径，以便 建立结构-活动关系，旨在创造更好的 治疗剂变得可用。