NEW SYNTHESIS OF REACTIONS FOR ACTIVE PRINCIPLES

描述(申请人提供)：在我们的实验室中，我们试图研究有机合成的潜在进展，并将这些进展应用于天然产品或具有新生物活性的天然产品同系物的阐述和研究。在HL 25848，我们将参与两个层次的项目。已经确定了一组新的靶点，它们大致属于非肽类神经营养因子的类别，用于全合成研究以及使用我们所称的转移全合成的SAR后续研究(见下文)。我们的目标是通过全合成，拥有一个具有神经营养活性的聚焦小分子文库。我们希望，在功能协作生物机制研究的背景下，这些合成计划将导致对神经退行性疾病的理解和治疗方面的真正进展。针对这一主题的新靶标包括：(I)卡布罗宁G甲酯，一种杂环二萜类化合物；(Ii)螺内酯A，一种新的螺环三环乙烷；(Iii)11-O-脱苯甲酰基塔希宁；(Iv)松内酯；(V)三氯苯丙内酯A；以及(Vi)山茉莉内酯A的两个对映体。此外，在这一授权期内，我们希望完成22-26间隔的几个目标系统。这些药物包括：(Vii)一种有效的PAF拮抗剂phomactin A；(Viii)一种新型的、高活性的PKC抑制剂xestcyclamine；以及两种复杂的抗肿瘤异喹啉生物碱，(Ix)ecteinassidin-743和(X)cribrostatin IV。在每一种情况下，只要天然产物的靶标已被证明具有前景和有用的活性，就将有重点、有针对性的合作生物后续研究寻求提供机制上的见解，以加强功能分析并评估进一步开发的潜力。

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.