Asymmetric Synthesis of Biological Active Amino Derivatives and Multi-target Drug

生物活性氨基衍生物及多靶点药物的不对称合成

• 批准号: 8772237
• 负责人: MARGARITA ORTIZ-MARCIALES
• 金额: $ 32.52万
• 依托单位: UNIVERSITY OF PUERTO RICO AT HUMACAO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772237
• 关键词: Adverse effects; Affect; Alcohols; Alzheimer' s Disease; Amines; Amino Acids; Amino Alcohols; Anesthetics; Anti-Arrhythmia Agents; Antibiotics; Antioxidants; Area; Benzazepines; Binding; Biological; Biomedical Research; Boranes; Boron Compounds; Chemicals; Cholinergic Agents; Computers and Advanced Instrumentation; Computing Methodologies; Degenerative Disorder; Development; Disadvantaged; Docking; Doctor of Philosophy; Drug Targeting; Education; Esters; Excision; Galantamine; Goals; Hand; Health; Heterocyclic Amines; Human; Hydrogenation; Isomerism; Ketones; Knowledge; Laboratories; Ligands; Mediating; Methodology; Methods; Mexiletine; Modeling; Molecular; Natural regeneration; Neurobiology; Neurodegenerative Disorders; Neurologic; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Organic Chemistry; Outcome; Oximes; Parkinson Disease; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Principal Investigator; Process; Prodrugs; Production; Property; Protocols documentation; Puerto Rico; Research; Resolution; Rest; Schools; Therapeutic; Training; Transition Elements; analog; biological systems; catalyst; cholinergic; cost effective; design; drug discovery; expectation; experience; inhibitor/antagonist; innovation; interest; novel; peptidomimetics; pressure; programs; small molecule; tool; undergraduate student

DESCRIPTION (provided by applicant): Our long term general goal is to develop novel organic synthetic methodologies for the preparation of potential nonracemic amino drugs that can affect different cholinergic pathways and have neuroprotective properties, which will be valuable for the treatment of neurodegenerative diseases. Nonracemic compounds, particularly non natural amino acids and heterocyclic amino compounds are important biologically active small molecules as drugs themselves, or as chiral building blocks for the synthesis of a variety of drugs. Non-natural amino alcohols and amino acids are important tools in drug discovery and when they are used in therapeutic peptidomimetics as chemical probes to understand the mechanism of biological systems. Thus, new suitable and facile asymmetric methods for the synthesis of these amino compounds are strongly needed. The main objective in this proposal is to design novel synthetic transformations using facile and environmentally friendly chiral boron compounds with high stereo-selectivity for the preparation of enantiopure key amino compounds. The previous expertise obtained in the enantioselective borane-mediated reductions catalyzed by novel aminoborate esters will be directed to: 1) To design new protocols for the asymmetric synthesis of novel amino alcohols, and non-natural amino acid and multi-functional amines with pharmaceutical potential. 2) To develop new multifunctional nicotine and benzazepine analogues for the treatment of neurodegenerative diseases such as Alzheimer's Disease. The synthetic aspects of these processes, including the structural factors affecting the reactivity and stereo chemical outcome, will be studied by computational methods. Thus, new large scale asymmetric methodologies will be established, particularly, for the synthesis of non-natural amino alcohols, amino acids and heterocyclic amino derivatives of neurological interest that will open new avenues to prepare important enantiopure non-natural peptides and other bioactive intermediaries. Likewise, this project will provide a positive impact on the education of a significant number of disadvantage undergraduate students from Puerto Rico offering them advanced knowledge and experience in synthetic organic and medicinal chemistry. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：我们的长期总体目标是开发新的有机合成方法来制备潜在的非外消旋氨基药物，这些药物可以影响不同的胆碱能途径并具有神经保护特性，这对于神经退行性疾病的治疗具有重要价值。非外消旋化合物，特别是非天然氨基酸和杂环氨基化合物是重要的生物活性小分子，作为药物本身，或作为合成多种药物的手性结构单元。非天然氨基醇和氨基酸是药物发现以及在治疗性肽模拟物中用作化学探针以了解生物系统机制的重要工具。因此，迫切需要新的合适且简便的不对称方法来合成这些氨基化合物。该提案的主要目标是设计新颖的合成转化，使用简便且环境友好的具有高立体选择性的手性硼化合物来制备对映体纯的关键氨基化合物。先前在新型氨基硼酸酯催化的对映选择性硼烷介导的还原中获得的专业知识将用于：1）设计用于不对称合成新型氨基醇、非天然氨基酸和具有药用潜力的多功能胺的新方案。 2）开发新型多功能尼古丁和苯并氮杂类似物，用于治疗阿尔茨海默病等神经退行性疾病。这些过程的合成方面，包括影响反应性和立体化学结果的结构因素，将通过计算方法进行研究。 因此，将建立新的大规模不对称方法，特别是用于合成具有神经学意义的非天然氨基醇、氨基酸和杂环氨基衍生物，这将为制备重要的对映体纯非天然肽和其他生物活性中间体开辟新途径。同样，该项目也将对儿童教育产生积极影响。 来自波多黎各的大量弱势本科生为他们提供合成有机和药物化学方面的先进知识和经验。 PHS 398/2590（修订版 06/09） 页面延续 格式页面