NEW SYNTHESIS OF REACTIONS FOR ACTIVE PRINCIPLES

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制备和研究。在HL 25848中，我们将从事两个级别的项目。已经确定了一组广泛属于非肽基神经营养因子类别的新靶点，用于全合成研究以及SAR随访研究，使用我们称之为转移的全合成（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小分子集中库。我们希望，这些合成程序，在功能合作的生物机制研究的背景下，将导致真实的进展，在理解和治疗神经退行性疾病。针对该基序的新靶点包括（i）毛茛宁G甲酯，一种杯烷型二萜;（ii）螺环毛茛碱A，一种新的螺环毛茛烷;（iii）11-O-脱苯甲酰基毛茛宁;（iv）terreulactone;（v）tricholomalide A;和（vi）merrilactone A的2个对映体。此外，在这个赠款期间，我们希望从22-26间隔关闭几个目标系统。其中包括：（vii）phomactin A，一种有效的PAF拮抗剂;（viii）xestocycline，一种新的和高活性的PKC抑制剂;和2种复合抗肿瘤异喹啉生物碱，（ix）海鞘素-743和（x）cribrostatin IV。在每一种情况下，天然产物目标已被证明表现出有前途的和有用的活动，将有重点的，目标明确的合作生物后续研究，寻求提供机制的见解，以增强功能测定和评估进一步发展的潜力。

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.