NEW METHODOLOGIES FOR THE SYNTHESIS OF AMINO DERIVATIVES AS NICOTINIC RECEPTOR

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。手性氨基衍生物是一类重要的有机化合物，已被用作合成多种药物的基础材料，并在许多烯烃类选择性有机制剂中用作助剂和催化剂。许多合成药物，特别是抗生素、氨基胺、α和β受体激动剂和拮抗剂，都含有带有氨基的手性碳中心。在我们的实验室里，我们正在开发合成氨基衍生物的新方法，这些方法可以用于制备生物活性分子。该项目的主要目标是开发新的有机合成方法来制备潜在的烟碱型乙酰胆碱受体(NAChRs)激动剂，该激动剂将对治疗阿尔茨海默病和帕金森等神经元退行性疾病具有价值。通过我们以前的研究，我们在合成和还原芳香族N-取代硅基、硅氧基、硼基和硼氧基亚氨基衍生物方面所获得的知识和专业知识将用于尼古丁类似物的合成。我们的目标是设计新型的手性有机硼烷试剂和合成体系，在所提出的有机转化中能够实现高的对映选择性或非对映选择性。本论文在已有的芳基烷基胺类化合物的合成和有机硼烷化学的基础上，研究了新的手性B-取代-L、3，2-恶唑硼烷和1，3，2-二氧硼杂环-H体系用于合成吡烷基甲烷氨基配体的发展和反应活性。将讨论这些过程的机械方面，包括影响反应性和立体化学结果的结构因素。此外，我们还将继续研究我们实验室发现的一种Beckman类型的重排反应，在该反应中，芳香族硅烷基肟转化为苯胺衍生物。该反应将用于合成烟碱受体的活性配体芳香族杂环胺和氨基取代吡啶。所提出的方法不仅有助于通过硼烷试剂进行新的有机反应，而且还将探索制备新型氨基吡啶衍生物的新途径，这些衍生物将被研究为潜在的尼古丁受体配体。为了实现上述目标，我们确定了以下具体目标：1.合成新的有机硼氢化物试剂，并通过B、C、H核磁共振波谱和X-射线分析对其进行了表征。2.考察了前手性模型N-取代亚胺与已合成的有机硼烷试剂的还原反应，并研究了影响立体选择性的结构因素。3.研究了B-取代-L，3，2-恶唑硼烷类化合物用于C-C键的形成以及随后的硼酸衍生物向氨基衍生物的转化。4.建立合成新的氨基吡啶和外消旋及富含对映体的芳基吡啶类烟碱受体激动剂的方法：5.研究吡啶取代亚胺的硼烷还原反应，以合成烷基和杂环氨基吡啶。6.利用电压钳技术和在卵母细胞中重组表达nAChRs，检测这些新的氨基吡啶、外消旋和富含对映体的芳基吡啶偏胺类化合物作为神经元尼古丁受体(NAChRs)的潜在激动剂。7.用分子模拟方法研究手性试剂和过渡态的最佳立体化学。分子模拟也将被用来建立激动剂结构与观察和计算的NACH受体亲和力之间的相关性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chiral amino derivatives are important organic compounds, which have been used as building blocks for the synthesis of a variety of pharmaceutical compounds and as auxiliaries and.catalysts in many enan!ioselective organic preparations. Many synthetic drugs, in particular, antibiotics, aministamines, alpha- and beta- adrenoreceptors agonists and antagonist, contain chiral carbons centers with amino groups. In our laboratory we are developing novel methods for the synthesis of amino derivatives that can be applied for the preparation of biologically active molecules. The main goal of this project is to develop novel organic synthetic methodology for the preparation of potential nicotinic acetyl choline receptor (nACHRs) agonist that will be valuable for the treatment of neuron-degenerative diseases, such Alzheimer and Parkinson. The acquired knowledge and expertise through our previous studies on the synthesis and reduction of aromatic N-substituted silyl-, silyloxy-, boryl- and boryloxy imino derivatives with boron reagents will be directed toward the synthesis of nicotine analogues. Our aim is to design novel chiral organoborane reagents and synthetic systems that can accomplish high enantioselectivities or diastereoselectivities in the proposed organic transformations. Based on our previous knowledge on the synthesis of arylalkyl amines and organoborane chemistry, we plan to investigated the development and reactivity of new chiral B-substituted-l,3,2-oxazaborolidines and 1,3,2-dioxaborinane-H systems for the synthesis of pyridylalky methanamino ligands. The mechanistic aspects of these processes including the structural factors affecting the reactivity and stereochemical outcome will be addressed. In addition, we will continue to study a Beckman type of rearrangement reaction of discovered in our laboratory, in which aromatic silylated oximes are converted to aniline derivatives. This reaction will be investigated for the synthesis of aromatic heterocyclic amines and amino substituted pyridines, which are active ligands for nicotinic receptors. The proposed methodology will not only contribute significantly, to the development of new organic reaction via borane reagents, but will also explore new routes for the preparation of novel amino pyridine derivatives that will be studied as potential nicotinic receptors ligands. To accomplish our previous stated goals, we have established the following specific objectives: 1. To prepare new organo-borohydride reagents and fully characterize them by B, C and H NMR spectra and X-ray analysis. 2. To investigate the reduction of prochiral model N-substituted-imines with borane and the previously prepared organoboranes reagents, and study the structural factor that affect the stereo-selectivity. 3. To study of use of B-substituted-l,3,2-oxazaborolidines for the C-C bond formation and subsequent transformation of the boronic acid derivatives to amino derivatives. 4. To establish protocols for the synthesis of new amino pyridine and racemic and enantio-enrich arylpyridylmetanamines as nicotinic receptor agonist: 5. To study the borane reduction of pyridyl substituted imines for the synthesis of alkyl and heterocyclic aminopyridines. 6. To test these new amino pyridine and racemic and enantio-enrich arylpyridylmetanamines as potential agonists for neuronal nicotinic receptors (nAChRs) using voltage clamp techniques and recombinant expression of nAChRs in oocytes. 7. To study the optimal stereochemistry of chiral reagents and transition states for the proposed enantioselective reactions using molecular modeling method. Molecular modeling will also be used to establish the correlation between agonist's structure and observed and calculated affinities for the nACH Receptor.