Cycloadditions and cycloreversions of pyrazinones: preparation of diverse medicin

吡嗪酮的环加成和环化回复：多种药物的制备

• 批准号: 8755465
• 负责人: Jonathan R Scheerer
• 金额: $ 29.4万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755465
• 关键词: 2-hydroxypyridine; Alkaloids; Alkenes; Alkynes; Area; Award; Biological; Biological Factors; Biomedical Research; Calmodulin; Camptothecin; Chemicals; Chemistry; Climate; Clinic; Colorectal Cancer; Complex; Development; Doctor' s Degree; Educational process of instructing; Environment; Exercise; Exhibits; Family; Goals; Health; Human; Investigation; Isocyanates; Lead; Learning; Medicine; Methodology; Methods; Preparation; Process; Production; Property; Pyridones; Reaction; Research; Research Personnel; Resources; Science; Structure; Sulfur; Targeted Research; Therapeutic; Time; Topotecan; Toxic effect; Training; United States National Institutes of Health; adduct; base; chemical reaction; chemotherapeutic agent; college; cost efficient; cycloaddition; cytotoxicity; diketopiperazine; drug candidate; drug development; experience; flexibility; irinotecan; polysulfide; programs; scaffold; tumor

DESCRIPTION (provided by applicant): The investigation of new chemical reactions that perform asymmetric transformations is a valuable exercise. The benefits of research in asymmetric synthesis are largely practical: the development of new methods leads to efficient and resourceful production of complex molecules of value. When this research effort is directed to the preparation of bioactive molecules, the exercise becomes acutely relevant to biomedical sciences and can directly impact human health. This proposal describes a unified research plan for the preparation of three important medicinally privileged structural motifs: [2.2.2]-diazabicyclic, 2-pyridone, and epipolythiodioxopiperazine (ETP) alkaloids. More than 70 distinct fungal metabolites (including the brevianamides, notoamides, and stephacidins) are now known to share in common the [2.2.2]-diazabicyclic core. Diverse biological activities including antihelmintic, antitumor, neuroprotective, calmodulin (CaM)-inhibition and insecticidal properties are observed across this natural product family. 2-pyridones are a ubiquitous functionality that has found widespread application in drug development and medicine. Camptothecin, one of the most well known natural products containing a 2-pyridone, is an important chemotherapeutic agent in the toolbox for the treatment of colorectal cancer. Synthetic research on camptothecin has delivered semi-synthetic derivatives (irinotecan and topotecan), which exhibit reduced toxicity and have replaced the natural product in the clinic. ETP alkaloids show varied and impressive bioactivities (most notably tumor selective, subnanomolar cytotoxicity) and have promising therapeutic potential. Current methods to prepare the polysulfide bridge require strongly acidic or basic conditions. We propose the direct entry to the ETP core (under neutral reaction conditions) by formal cycloaddition with diatomic sulfur. The research plan described in this proposal will enable new methods to prepare [2.2.2]- diazabicyclic, 2-pyridone, and ETP structures from a common intermediate, a 2,5-diketopiperazine azadiene (pyrazinone) precursor. Additionally, we are pursuing domino or "one- pot" reaction methodology for the preparation of these structures, an effort that is economical with regard to our time as researchers, but also resource and cost efficient and has the greatest opportunity to streamline research into both known bioactive molecules and new chemical space. Our research efforts will also contribute broadly to fundamental chemical understanding of the reactivity and selectivity of underexplored reactions. The College of William & Mary does not offer a doctoral degree in chemistry (BS/MS only); accordingly, my research group is composed of undergraduate researchers (and one MS candidate). My current research program creates a rigorous environment for discovery-based learning and enforces teaching and training in the one-on-one research experience. The proposed research would continue within this climate. Support from the NIH would enable the research of 4 undergraduates and one Master's candidate for each year of the award.

描述（由申请人提供）：对进行不对称转化的新化学反应的研究是一项有价值的练习。不对称合成研究的好处在很大程度上是实用的：新方法的开发可以高效、资源地生产有价值的复杂分子。当这项研究工作针对生物活性分子的制备时，这项研究就与生物医学密切相关，并且可以直接影响人类健康。该提案描述了一个统一的研究计划，用于制备三种重要的医学上特有的结构基序：[2.2.2]-二氮杂双环、2-吡啶酮和表聚硫二氧代哌嗪（ETP）生物碱。目前已知超过 70 种不同的真菌代谢物（包括 brevianamides、notoamides 和 Stephacidins）具有共同的 [2.2.2]-二氮杂双环核心。该天然产品家族具有多种生物活性，包括抗蠕虫、抗肿瘤、神经保护、钙调蛋白 (CaM) 抑制和杀虫特性。 2-吡啶酮是一种普遍存在的功能，在药物开发和医学中得到广泛应用。喜树碱是最著名的含有 2-吡啶酮的天然产物之一，是治疗结直肠癌的重要化疗剂。喜树碱的合成研究已经产生了半合成衍生物（伊立替康和托泊替康），其毒性降低，并在临床上取代了天然产物。 ETP 生物碱表现出多种令人印象深刻的生物活性（最显着的是肿瘤选择性、亚纳摩尔细胞毒性），并具有广阔的治疗潜力。目前制备多硫桥的方法需要强酸性或碱性条件。我们建议通过与双原子硫的正式环加成直接进入ETP核心（在中性反应条件下）。该提案中描述的研究计划将使新方法能够从常见中间体（2,5-二酮哌嗪氮杂二烯（吡嗪酮）前体）制备[2.2.2]-二氮杂双环、2-吡啶酮和ETP结构。此外，我们正在寻求多米诺骨牌或“一锅”反应方法来制备这些结构，这种努力不仅节省了我们作为研究人员的时间，而且还具有资源和成本效益，并且有最大的机会简化对这两方面的研究。已知的生物活性分子和新的化学空间。我们的研究工作还将广泛有助于对尚未探索的反应的反应性和选择性的基本化学理解。威廉玛丽学院不提供化学博士学位（仅限 BS/MS）；因此，我的研究小组由本科生研究人员（和一名硕士研究生）组成。我目前的研究计划为基于发现的学习创造了一个严格的环境，并以一对一的研究经验加强教学和培训。拟议的研究将在这种气氛下继续进行。 NIH 的支持将使每年的 4 名本科生和 1 名硕士候选人能够进行研究。