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）：进行不对称转化的新化学反应的研究是一项有价值的工作。不对称合成研究的好处主要是实用的：新方法的开发导致有价值的复杂分子的高效和资源丰富的生产。当这项研究工作针对生物活性分子的制备时，这项工作就与生物医学科学密切相关，并直接影响人类健康。该提案描述了一个统一的研究计划，用于制备三个重要的药用特权结构基序：[2.2.2]-二氮杂双环，2-吡啶酮和epipolythiodioxipipiperazine（ETP）生物碱。现在已知有超过70种不同的真菌代谢物（包括brevianamides、notoamides和stephacidins）共享共同的[2.2.2]-二氮杂双环核心。在该天然产物家族中观察到多种生物活性，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官能团，其在药物开发和医学中具有广泛的应用。喜树碱是最著名的含有2-吡啶酮的天然产物之一，是用于治疗结直肠癌的工具箱中的重要化疗剂。对喜树碱的合成研究已经提供了半合成衍生物（伊立替康和拓扑替康），其表现出降低的毒性，并在临床上取代了天然产物。ETP生物碱显示出多种多样且令人印象深刻的生物活性（最显著的是肿瘤选择性、亚纳摩尔细胞毒性），并且具有有希望的治疗潜力。目前制备多硫化物桥的方法需要强酸性或碱性条件。我们建议直接进入ETP核心（在中性反应条件下）通过正式环加成与双原子硫。本提案中描述的研究计划将使新的方法能够从一个共同的中间体，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“一锅法”反应方法来制备这些结构，这一努力对于我们作为研究人员的时间来说是经济的，但也是资源和成本有效的，并且有最大的机会简化对已知生物活性分子和新化学空间的研究。我们的研究工作也将有助于广泛的基础化学的反应性和选择性的未充分探索的反应的理解。威廉和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研究人员（和一名MS候选人）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，并在一对一的研究经验中实施教学和培训。拟议的研究将在这种气候下继续进行。从美国国立卫生研究院的支持将使研究的4个本科生和一个硕士候选人每年的奖项。