New Synthetic Reactions For Active Principles

活性原理的新合成反应

• 批准号: 8125122
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 44.78万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-01-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125122
• 关键词: AIDS Vaccines; Adrenal Cortex Hormones; Aldosterone; Area; Back; Biological; Biological Factors; Cancer Vaccines; Carbohydrates; Chemistry; Cognitive; Development; Diels Alder reaction; 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

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(由申请者提供)：我们最早的项目可以追溯到匹兹堡大学PI的实验室。起初，它完全是针对在逻辑和方法论方面的有机合成的进展图表。然后，它演变成耶鲁大学的一项更广泛的努力，寻求利用合成方面的进展来获得小分子天然产品(SMNPs)，并利用其对此类SMNPs的完全合成。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流时，HL 25848被转移到哥伦比亚大学。两笔由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续期是我们将在HL 25848上承担的最后一次延期。虽然我们的实验室仍然保持着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是合适的，他们将追求令人兴奋的新方向。我们寻求这一更新的目标有几个。首先，我们相信，它将促进具有智力价值和翻译层面兴趣的研究。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在这里的项目，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对他们的职业发展。该计划分布在十个项目中，我们认为这些项目可以在指定的时间框架内掌握。项目d1-d4设想了关于Diels Alder反应的传统思维的重大新变化。项目d1利用Diels Alder反应来达到迄今通过羰基缩合反应构建的体系。项目D2将DA反应与其他化学结合起来，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一种途径。D3项目在分子内Diels Alder反应(IMDA)的背景下实现了范式转变。项目D4利用从d1到d3的进展来完成高活性皮质类固醇的新的全合成。项目D5至D8具有很强的药学相关性。因此，D5项目寻求在具有神经营养活性的SMNPs的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项目建立在我们合成的一种红参化合物的基础上。我们已经取得了一种预防癌症的候选结构。项目D7和D8建立在我们最近完成的ET-743和多黄黄素A的全合成基础上，这导致了一些有趣和意想不到的SAR发现。项目D9有望在取得重大进展后完成三氯马利德A的全合成，尽管仍有许多工作要做。D10项目设想了一种新的加地芬宁的全合成(基于新的化学)，其类似物似乎在未来的发展中非常有希望。公共卫生相关性：我们的计划旨在研究有机合成方面的潜在进展，并将这些进展应用于小分子天然产品(SMNP)或具有新生物活性的天然产品同系物的精制和研究。在HL 25848上，我们将参与三个层面的工作，i)针对合成方法学的计划；ii)针对药物化学的另一项努力；以及iii)针对生物活性SMNPs全合成中两个具有挑战性的问题的计划。