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

Public Health Relevance

The proposed R15 project, entitled: 'Asymmetric Synthesis of Biological Active Amino Derivatives and Multi-target Drugs for the Treatment of Alzheimer's Disease', aims to develop novel asymmetric large-scale syntheses that will open new avenues to prepare directly by a green and facile methodology a variety of important enantiopure primary non-natural amino alcohols and amino acids of important pharmaceutical interest. Moreover, our major goal is to design and efficiently prepare by innovative methods novel multi-target benzazepine and nicotine analogues for the treatment of neuron-degenerative diseases, such as Alzheimer and Parkinson. Additionally, the proposed research will strongly enhance education in biomedical research among underrepresented undergraduate students in Puerto Rico.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of Puerto Rico at Humacao
Schools of Arts and Sciences
United States
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