NEW SYNTHESIS OF REACTIONS FOR ACTIVE PRINCIPLES

活性原理反应的新综合

• 批准号: 7088767
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 44.53万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088767
• 关键词: alkaloids; biological products; chemical registry /resource; chemical structure function; chemical synthesis; combinatorial chemistry; diterpenes; drug discovery /isolation; kinase inhibitor; lactones; neurotrophic factors; receptor binding; small molecule; stereochemistry

DESCRIPTION (provided by applicant): In our laboratory we seek to study potential advances in organic synthesis and to apply such advances to the elaboration and study of natural products or natural product congeners of novel biological activity. In HL 25848, we will be engaged in projects at 2 levels. A group of new targets which fall broadly in the category of non-peptidyl neurotrophic factors has been identified for total synthesis studies as well as SAR follow-up studies using what we term as diverted total synthesis (vide infra). Our goal is to have at our disposal, through total synthesis, a focused library of small molecules with neurotrophic activity. We hope that these synthesis programs, in the context of functional collaborative bio-mechanistic studies, will lead to real progress in the understanding and treatment of neurodegenerative diseases. The new targets directed to this motif include (i) scabronine G methyl ester, a cyathane diterpene; (ii) spirotenuipesine A, a novel spirocyclic trichothecane; (iii) 11-O-debenzoyltashironin; (iv) terreulactone; (v) tricholomalide A; and (vi) the 2 antipodes of merrilactone A. In addition, in this grant period, we hope to bring to closure several goal systems from the 22-26 interval. These include: (vii) phomactin A, a potent PAF antagonist; (viii) xestocyclamine, a novel and highly active PKC inhibitor; and 2 complex antitumor isoquinolinoid alkaloids, (ix) ecteinascidin-743 and (x) cribrostatin IV. In each case where the natural product target has been shown to exhibit promising and useful activity, there will be focused, well-aimed collaborative biological follow-up studies seeking to provide mechanistic insights to augment functional assays and to evaluate potential for further development.

描述（由申请人提供）：在我们的实验室中，我们寻求研究有机合成的潜在进展，并将这些进展应用于天然产物或具有新生物活性的天然产物同系物的阐述和研究。在HL 25848中，我们将从事2个级别的项目。一组广泛属于非肽基神经营养因子类别的新靶标已被确定用于全合成研究以及SAR后续研究，我们称之为转移全合成（vide infra）。我们的目标是，通过全合成，拥有一个集中的具有神经营养活性的小分子库。我们希望在功能性协同生物机制研究的背景下，这些合成程序将导致对神经退行性疾病的理解和治疗取得真正的进展。指向该基序的新靶标包括(i)氨基二萜-氨基丙烷G甲酯；（ii）螺环菌素A，一种新型螺环菌链；(3) 11-O-debenzoyltashironin;(四)terreulactone;(v) tricholomalide A；（vi） merilactone a的2个对跖点。此外，在此资助期内，我们希望完成22-26区间的几个进球系统。这些包括：（vii） phomactin A，一种有效的PAF拮抗剂；（viii） xestocyclamine，一种新型的高活性PKC抑制剂；以及2种复杂的抗肿瘤异喹啉类生物碱，（ix） ecteinascidin-743和(x) cribrostatin IV。在每种情况下，天然产物靶点已显示出有希望和有用的活性，将有重点，目标明确的合作生物学后续研究，寻求提供机制见解，以增强功能分析并评估进一步开发的潜力。