Synthesis and study of oxo-bridged taxanes by C-C activation/cross-coupling of carvone-derived cyclobutanols

香芹酮衍生环丁醇的 C-C 活化/交叉偶联合成和研究氧桥紫杉烷

• 批准号: 9568336
• 负责人: Nicholas Ryan O'Connor
• 金额: $ 2.12万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-16 至 2019-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9568336
• 关键词: 3-hydroxybutanal; Address; Alkenes; Antimitotic Agents; Betula Genus; Binding; Biological; Caring; Cessation of life; Chemistry; Collaborations; Complex; Coupling; Development; Disease; Diterpenes; Event; Exhibits; Generations; Hybrids; Laboratories; Ligands; Light; Malignant Neoplasms; Methodology; Methods; Microtubule Stabilization; Microtubules; Molecular Conformation; Natural Products; Nature; Paclitaxel; Palladium; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Privatization; Property; Reaction; Research; Resistance; Route; Scheme; Series; Solubility; Structure; Structure-Activity Relationship; Terpenes; Therapeutic; Therapeutic Agents; United States National Institutes of Health; analog; aqueous; base; cancer therapy; chemotherapeutic agent; cytotoxic; cytotoxicity; design; insight; lipophilicity; next generation; novel; oxidation; scaffold; screening program; taxane; tumor

PROJECT SUMMARY/ABSTRACT Cancers are serious and highly prevalent diseases, with an estimated 14 million new cases and 8.2 million deaths worldwide in 2012. Among the wide variety of chemotherapeutic agents, taxane drugs like paclitaxel (Taxol®) have emerged as standards of care for the treatment of certain cancers. Unfortunately, the utility of these drugs is limited by their pronounced lipophilicity and the recent emergence of resistant cancers, creating an urgent need for novel taxane chemotherapeutics. This proposal describes a plan to synthesize the taxane molecule taxagifine, as well as structurally related natural and unnatural taxanes, in an effort to provide new compounds for biological study. Taxagifine exhibits promising microtubule-stabilizing and cytotoxic properties and demonstrates potential activity against resistant cancers, but differs structurally from paclitaxel at several positions, including an unusual C17–C12 oxo-bridge functionality which will likely impart increased aqueous solubility relative to paclitaxel. Further studies of taxagifine have been frustrated by a lack of material: isolation from nature is extremely inefficient, and the C17–C12 oxo-bridge poses a significant challenge to any semi-synthetic routes. This proposal describes the first total synthetic approach to taxagifine and related compounds, with the hypothesis that the expansion of Sarpong's C–C activation/arylation reaction of carvone-derived cyclobutanols will enable a concise, convergent, and scalable synthesis of taxagifine. The Specific Aims of the proposal are: 1) Expansion of the C–C activation/arylation methodology recently developed by Sarpong and co-workers to allow for the use of synthetically versatile vinyl electrophiles, 2) Apply the C–C activation/vinylation reaction developed in Aim I to the construction of the oxo-bridged A ring and subsequently the total synthesis of taxagifine, and 3) Use the concise route to taxagifine developed in Aim II to make other natural taxanes containing the C17–C12 oxo-bridge, as well as unnatural taxagifine derivatives for structure-activity- relationship (SAR) studies. Our syntheses of unnatural analogs will focus on exploiting the synthetic route to install functionalization at underexplored positions on the taxagifine framework. The synthesis of paclitaxel- taxagifine hybrids will also be investigated to probe the taxagifine binding conformation. The development of a C–C activation/vinylation reaction will allow for the construction of a diverse array of terpenoid scaffolds, with potential use in medicinal chemistry and natural products total synthesis. Use of this reaction to synthesize taxagifine as well as natural and unnatural analogs will enable SAR and mechanism of action studies, furthering our understanding of microtubule-interactions and helping to identify potential second generation taxane therapeutic agents.

项目总结/摘要 癌症是严重和高度流行的疾病，估计有1400万新病例和820万 2012年全球死亡人数在种类繁多的化疗药物中，紫杉烷类药物如紫杉醇 （Taxol®）已经成为治疗某些癌症的护理标准。不幸的是， 这些药物受到其明显的亲脂性和最近出现的耐药癌症的限制， 迫切需要新的紫杉烷化疗剂。该提案描述了一个合成紫杉烷的计划 分子taxagifine，以及结构上相关的天然和非天然紫杉烷，努力提供新的 用于生物学研究的化合物。紫杉芬具有良好的微管稳定性和细胞毒性 并显示出对抗耐药癌症的潜在活性，但在结构上与紫杉醇在几个方面不同， 位置，包括不寻常的C17-C12氧代桥官能团，其可能赋予增加的水性 相对于紫杉醇的溶解度。对taxagifine的进一步研究因缺乏材料而受挫： 与自然隔离是非常低效的，C17-C12氧桥对任何人都构成了重大挑战。 半合成路线。 该提案描述了taxagifine和相关化合物的第一种全合成方法， 假设Sarpong的香芹酮衍生的环丁醇的C-C活化/芳基化反应的扩展 将能够实现简洁、收敛和可扩展的紫杉芬合成。该提案的具体目标是： 1)Sarpong及其同事最近开发的C-C活化/芳基化方法的扩展， 允许使用合成通用的乙烯基亲电试剂，2）应用C-C活化/乙烯化反应 在目的I中开发的氧代桥连A环的构建和随后的全合成 taxagifine，和3）使用Aim II中开发的taxagifine的简洁路线来制备其他天然紫杉烷 含有C17-C12氧代桥，以及非天然的taxagifine衍生物的结构-活性- 关系（SAR）研究。我们的非天然类似物的合成将集中在利用合成路线， 在taxagifine框架中未充分开发的位置安装功能化。紫杉醇的合成- 还将研究紫杉烷杂合体以探测紫杉烷结合构象。 C-C活化/乙烯基化反应的发展将允许构建各种各样的聚合物。 萜类化合物支架，在药物化学和天然产物全合成中具有潜在的应用。使用本 合成taxagifine以及天然和非天然类似物的反应将使SAR和机制成为可能。 行动研究，进一步了解微管相互作用，并帮助确定潜在的第二个 一代紫杉烷类治疗剂。