NEW METHODOLOGIES FOR THE SYNTHESIS OF AMINO DERIVATIVES AS NICOTINIC RECEPTOR

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 手性氨基衍生物是重要的有机化合物，其已用作合成多种药物化合物的结构单元以及用作许多对映选择性有机制剂中的助剂和催化剂。许多合成药物，特别是抗生素、阿米尼胺、α-和β-肾上腺素受体激动剂和拮抗剂，都含有带有氨基的手性碳中心。在我们的实验室中，我们正在开发合成氨基衍生物的新方法，该方法可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乙酰胆碱受体（nACHR）激动剂，这对于治疗神经元退行性疾病（如阿尔茨海默病和帕金森病）具有重要价值。我们之前通过硼试剂合成和还原芳香族N-取代甲硅烷基、甲硅烷氧基、硼酰基和硼酰氧基亚氨基衍生物的研究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手性有机硼烷试剂和合成系统，以在所提出的有机转化中实现高对映选择性或非对映选择性。基于我们先前对芳烷基胺合成和有机硼烷化学的了解，我们计划研究用于合成吡啶烷基甲氨基配体的新型手性B-取代-1,3,2-恶唑硼烷和1,3,2-二氧杂硼烷-H体系的开发和反应性。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，我们将继续研究我们实验室发现的贝克曼型重排反应，其中芳香族甲硅烷基化肟转化为苯胺衍生物。该反应将用于合成芳香杂环胺和氨基取代的吡啶，它们是烟碱受体的活性配体。所提出的方法不仅将为通过硼烷试剂开发新的有机反应做出重大贡献，而且还将探索制备新型氨基吡啶衍生物的新路线，这些衍生物将作为潜在的烟碱受体配体进行研究。 为了实现我们之前提出的目标，我们制定了以下具体目标 目标： 1. 制备新型有机硼氢化物试剂，并通过B、C、H NMR谱和X射线分析对其进行充分表征。 2. 研究硼烷和预先制备的有机硼烷试剂对前手性模型N-取代亚胺的还原反应，并研究影响立体选择性的结构因素。 3.研究B-取代的-1,3,2-恶唑硼烷用于C-C键的形成以及随后硼酸衍生物向氨基衍生物的转化。 4. 建立新型氨基吡啶和外消旋体的合成方案 作为烟碱受体激动剂的对映体富集的芳基吡啶基甲胺： 5. 研究吡啶基取代亚胺的硼烷还原反应合成烷基和杂环氨基吡啶。 6. 测试这些新的氨基吡啶以及外消旋和对映体富集 使用电压钳技术和卵母细胞中 nAChR 的重组表达，将芳基吡啶基甲胺作为神经元烟碱受体 (nAChR) 的潜在激动剂。 7. 利用分子建模方法研究所提出的对映选择性反应的手性试剂和过渡态的最佳立体化学。分子模型还将用于建立激动剂结构与观察到和计算出的 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.