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New Synthetic Reactions For Active Principles

活性原理的新合成反应

基本信息

批准号：
8310995
负责人：
SAMUEL J DANISHEFSKY
金额：
$ 51.57万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8310995
关键词：
AIDS Vaccines Adrenal Cortex Hormones Aldosterone Area Back Biological Biological Factors Cancer Vaccines Carbohydrates Chemistry Cognitive Development Diels Alder reaction Diet Elements Enzymes Erythropoietin Evaluation Follicle Stimulating Hormone Fostering Funding Future Generations Ginseng Preparation Glycoproteins Goals Grant Health Housing Institutes Laboratories Logic Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Methodology Methods Neurodegenerative Disorders Organic Synthesis Pattern Pharmaceutical Chemistry Pharmacologic Substance Physical condensation Process Reaction Reporting Research Route Science Scientist Screening procedure Source Steroids Structure Synthesis Chemistry System Therapeutic Thinking Time Translations Universities Work analog base career chemical synthesis cycloaddition disorder prevention drug discovery graduate student innovation interest meetings method development novel programs small molecule tricholomalide A

项目摘要

DESCRIPTION (provided by applicant): Our earliest program goes back to the PI's laboratory at the University of Pittsburgh. At first, it was entirely directed to charting advances in organic synthesis both as to logic and methodology. It then evolved into a broader effort at Yale Univeristy seeking to use advances in synthesis to arrive at small molecule natural products (SMNPs) and to exploit its total syntheses of such SMNPs. When our laboratory moved to NYC and bifurcated between Memorial Sloan-Kettering Cancer Center and the Department of Chemistry at Columbia Univeristy, HL 25848 was transferred to Columbia. Two cancer driven grants support our work at MSKCC. The renewal we seek at Columbia is the last we shall undertake on HL 25848. While our laboratory remains fully productive and competitive, we recognize the appropriateness of making way for a new generation of scientists, who will pursue exciting new directions. Our goals in seeking this renewal are several. First, we are convinced that it will foster research which will be intellectually valuable and also of interest of the translational level. Moreover, being the sole source of support for our Columbia program, it will enable us to bring our program here to an orderly conclusion while meeting commitments to various graduate students and postdoctorals, both for their research and in their career enhancement. The program is distributed among ten projects which, we think, can be mastered in the indicated time frame. Projects D1-D4 envision major new departues from conventional thinking about the Diels Alder reaction. Project D1 utilizes the Diels Alder reaction to reach systems hitherto constructed through carbonyl condensation reactions. Project D2 combines the DA reaction with other chemistry to reach trans fused junctions, whereas the classical DA reaction traditionally is seen as a route to cis fusions. Project D3 achieves the paradigm shift in the context of the intramolecular Diels Alder reaction (IMDA). Project D4 utilizes the advances from D1 through D3 to accomplish a new total synthesis of highly active corticosteroids. Projects D5 through D8 have strong elements of pharmaceutical relevance. Thus, project D5 seeks to find development candidates in the context of SMNPs with neurotrophic activity, the ultimate goal being application to neurodegenerative diseases. Project D6 builds from our synthesis of a compound in red ginseng. We have moved on to obtain a candidate structure for carcinoprevention. Projects D7 and D8 build from our recently completed total syntheses of ET-743 and pluraflavin A which led to some interesting and unexpected SAR findings. Project D9 involves, hopefully, the completion of the total synthesis of tricholomalide A following significant advances, though much remains to be done. Project D10 envisions a fresh total synthesis (based on new chemistry) of jiadifenin, analogs of which seem very promising for future development. PUBLIC HEALTH RELEVANCE: Our program seeks to study potential advances in organic synthesis and to apply such advances to the elaboration and study of small molecule natural products (SMNP) or natural product congeners of novel biological activity. In HL 25848, we will be engaged at three levels, i) a program directed to synthetic methodology; ii) another effort will be directed to medicinal chemistry, and iii) a program directed to two challenging problems in total synthesis of bioactive SMNPs.

描述（由申请人提供）：我们最早的项目可以追溯到匹兹堡大学的 PI 实验室。起初，它完全旨在描绘有机合成在逻辑和方法方面的进展。随后，它演变为耶鲁大学的一项更广泛的努力，寻求利用合成方面的进步来获得小分子天然产物 (SMNP)，并利用其对此类 SMNP 的全合成。当我们的实验室搬到纽约并在纪念斯隆-凯特琳癌症中心和哥伦比亚大学化学系之间分叉时，HL 25848 被转移到哥伦比亚。两项癌症驱动的赠款支持我们在 MSKCC 的工作。我们在哥伦比亚寻求的更新是我们对 HL 25848 进行的最后一次。虽然我们的实验室仍然保持充分的生产力和竞争力，但我们认识到为新一代科学家让路的适当性，他们将追求令人兴奋的新方向。我们寻求这种更新的目标有几个。首先，我们相信它将促进具有智力价值且对翻译水平感兴趣的研究。此外，作为我们哥伦比亚项目的唯一支持来源，它将使我们能够有序地结束我们的项目，同时履行对各种研究生和博士后的承诺，无论是对他们的研究还是职业发展。该计划分布在十个项目中，我们认为可以在指定的时间范围内掌握这些项目。项目 D1-D4 设想与关于第尔斯阿尔德反应的传统思维有重大新的不同。项目 D1 利用 Diels Alder 反应来实现迄今为止通过羰基缩合反应构建的系统。 D2 项目将 DA 反应与其他化学反应结合起来以达到反式融合连接，而经典的 DA 反应传统上被视为顺式融合的途径。 D3 项目在分子内第尔斯阿尔德反应 (IMDA) 的背景下实现了范式转变。 D4项目利用D1到D3的进步来完成高活性皮质类固醇的新全合成。项目 D5 至 D8 具有很强的制药相关性。因此，D5 项目寻求在具有神经营养活性的 SMNP 背景下寻找开发候选者，最终目标是将其应用于神经退行性疾病。 D6 项目是由我们在红参中合成一种化合物而构建的。我们已经开始获得预防癌症的候选结构。项目 D7 和 D8 基于我们最近完成的 ET-743 和多黄素 A 的全合成，这导致了一些有趣且意想不到的 SAR 发现。 D9 项目有望在取得重大进展后完成三氯苹果内酯 A 的全合成，但仍有许多工作要做。 D10 项目设想了一种全新的 jiadifenin 全合成（基于新化学），其类似物似乎在未来的发展中非常有前景。公共健康相关性：我们的计划旨在研究有机合成的潜在进展，并将这些进展应用于小分子天然产物 (SMNP) 或具有新型生物活性的天然产物同系物的阐述和研究。在 HL 25848 中，我们将在三个层面上开展工作，i）针对合成方法学的计划； ii) 另一项工作将针对药物化学，以及 iii) 一项针对生物活性 SMNP 全合成中两个挑战性问题的计划。

项目成果

期刊论文数量（60）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

(3R, 9R, 10R)-Panaxytriol: A molecular-based nutraceutical with possible application to cancer prevention and treatment.

DOI：
10.1016/j.tetlet.2008.09.169
发表时间：
2008-12-08
期刊：
TETRAHEDRON LETTERS
影响因子：
1.8
作者：
Ng, Fay;Yun, Heedong;Lei, Xiaoguang;Danishefsky, Samuel J.;Fahey, Jed;Stephenson, Katherine;Flexner, Charles;Lee, Lawrence
通讯作者：
Lee, Lawrence

Toward the total synthesis of maoecrystal V: an intramolecular Diels-Alder route to the maoecrystal V pentacyclic core with the appropriate relative stereochemistry.