GAP Chemistry Approaches to Chiral Amino Acids, Peptides and Peptidomimetics

描述（由申请人提供）：PI的小组最近建立了GAP（基团-辅助-纯化）化学的新概念;差距化学表明可以在不使用色谱和结晶的情况下实现氨基化合物的有机合成。该ECHEM提案计划探索差距化学，用于一系列非天然氨基酸和-和-氨基膦酸酯的不对称合成，以用于神经药物的设计和合成。差距化学也将有利于神经肽和一般肽以及肽模拟物的合成，以避免传统固相肽合成（SPPS）和液相肽合成的缺点。液相多肽合成（LPPS）是一种混合技术，但该方法仅适用于简单的酰胺键合成，模板分子量过大，不利于大量生产;通常需要长时间来产生结晶前体和产物（有时，甚至需要一周）通过仔细控制固化/结晶条件。相比之下，本项目差距化学工具将具有固相肽合成（SPPS）、液相肽合成（SoPPS）和液相肽合成（LPPS）的优势，包括通过过滤进行快速纯化，潜在的自动手动选项（对于SPPS）;易于从mg扩大到kg，并且不需要过量的试剂或昂贵的仪器（对于SoPPS和LPPS）。到目前为止，一种有效的方法，使不对称合成，随后肽合成还没有记录。在该ECHEM项目中，从差距合成中得到的由N-膦酰基和N-氧膦基部分连接的特殊手性氨基酸可用于设计和合成重要的药物滥用相关靶标，如神经肽、N-花生四烯酰基-Gly衍生物、N-花生四烯酰基乙醇胺、加压素和神经降压素类似物。PI小组取得的令人鼓舞的初步结果使这一建议可行。在过去的14年里，PI培养了近60名本科生和18名研究生（包括5名中国合作毕业生，其中一名是中国化学奥林匹克金牌得主）进行有机和生物有机/医学研究。所有这些毕业生和近30名本科生作为PI的合著者发表了研究论文，并成功找到了专业职位。 公共卫生相关性：本研究旨在探索非天然氨基酸和-氨基膦酸的不对称合成新策略，用于神经药物的设计和合成。GAP化学的新概念也被应用于神经肽和肽模拟物的合成，以使这些合成对环境友好，而无需繁琐的后处理。差距肽合成可以避免已知方法的缺点。PI的实验室已经获得了初步的结果，这使得这一建议是可行的。迄今为止，PI的团队已经培训了近60名本科生和18名研究生进行有机/药物研究，其中包括一名中国化学奥林匹克金牌得主。所有的毕业生和近30名本科生实现了PI的研究出版物。所有这些学生要么成功进入医学院，要么在制药公司找到工作。

DESCRIPTION (provided by applicant): The novel concept of GAP (Group-Assistant-Purification) chemistry has been established recently by the PI's group; the GAP chemistry shows organic synthesis of amino compounds can be achieved without the use of chromatography and crystallization. This ECHEM proposal is planned to explore the GAP chemistry for asymmetric synthesis of a series of unnatural amino acids and - and -amino phosphonates to serve for neuro drug design and synthesis. The GAP chemistry will also benefit the synthesis of neuro and general peptides and peptidomimetics as to avoid the disadvantages of traditional solid-phase-peptide synthesis (SPPS) and solution-phase-peptide synthesis. Although the liquid-phase-peptide synthesis (LPPS) was developed as a hybrid technique, this method was only suitable for simple amide bond formations for peptide synthesis; it suffers from the extremely large molecular weight of template which makes it inconvenient to produce large amounts of products; a long period is often needed to generate crystalline precursors and products (sometimes, it even takes one week) by carefully controlling solidification/crystalization conditions. In contrast, the GAP chemistry tool for this project will have advantages of solid-phase-peptide synthesis (SPPS), solution-phase-peptide synthesis (SoPPS) and liquid-phase-peptide synthesis (LPPS) including quick purification by filtration, a potential automated manual option (for SPPS); easy scale-up from mg to kg, and there is no need for excess amounts of reagents or expensive instrument (for SoPPS and LPPS). So far, an efficient method which enables asymmetric synthesis subsequently followed by peptide synthesis not been documented yet. In this ECHEM project, the resulting special chiral amino acids attached by N- phosphonyl and N-phosphinyl moieties from the GAP synthesis can be utilized for the design and synthesis of important drug abuse related targets, such as neuropeptides,N-arachidonoyl-Gly derivatives, N-arachidonoyl enthanolamines,hemopressin and neurotensin analogs. Promising preliminary results obtained by the PI's group make this proposal feasible. In the past 14 years, the PI has trained nearly 60 undergraduate students and 18 graduates (including 5 collaborative graduates in China, one of them is a Chinese Olympic gold medalist on chemistry) on conducting organic and bioorganic/medicinal research. All of these graduates and nearly 30 undergraduates achieved research publications as co-authors with the PI and successfully found professional positions. PUBLIC HEALTH RELEVANCE: This proposal is planned to explore novel strategies for the asymmetric synthesis of unnatural amino acids, and -amino phosphonic acids for neuro drug design and synthesis. A new concept of GAP chemistry is also applied to the synthesis of neuro peptides and peptidomimetics to make these syntheses environmentally friendly without tedious work-up. The GAP peptide synthesis can avoid disadvantages of known methods. The preliminary results have been obtained in the PI's lab, which makes this proposal feasible. Thus far, the PI's group has trained nearly 60 undergraduate students and 18 graduates in conducting research in organic/medicinal research including a Chinese Olympic Gold Medalist on Chemistry. All graduates and nearly 30 undergraduates achieved research publications with the PI. All of these students either successfully entered medical schools or found jobs in pharmaceutical companies.