GAP Chemistry Approaches to Chiral Amino Acids, Peptides and Peptidomimetics

描述（由申请人提供）：最近由PI小组建立了GAP （group - assistant - purification）化学的新概念；GAP化学表明，有机合成氨基化合物可以不使用色谱和结晶。本ECHEM提案计划探索GAP化学不对称合成一系列非天然氨基酸和-氨基膦酸盐，为神经药物的设计和合成服务。GAP化学还将有利于神经肽、一般肽和拟肽的合成，以避免传统固相肽合成（SPPS）和固相肽合成的缺点。虽然液相多肽合成（LPPS）是一种杂交技术，但这种方法只适用于合成简单的酰胺键；模板分子量大，不便于大批量生产；通过仔细控制凝固/结晶条件，通常需要很长一段时间来生成结晶前体和产品（有时甚至需要一周）。相比之下，本项目的GAP化学工具将具有固相肽合成（SPPS）、溶液相肽合成（SoPPS）和液相肽合成（LPPS）的优势，包括通过过滤快速纯化，这是一种潜在的自动化手动选择（用于SPPS）；易于从mg放大到kg，并且不需要过量的试剂或昂贵的仪器（用于SoPPS和LPPS）。到目前为止，一种有效的方法，使不对称合成随后跟随肽合成尚未被记录。在本ECHEM项目中，由GAP合成的N-膦基和N-膦基部分附着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点，如神经肽、N-花生四烯醇基甘氨酸衍生物、N-花生四烯醇基乙醇胺、加压素和神经紧张素类似物。PI小组获得的有希望的初步结果使这一建议可行。在过去的14年里，学院培养了近60名本科生和18名研究生（其中中国合作毕业生5名，其中一名是中国奥运化学金牌获得者）进行有机和生物有机/医学研究。这些毕业生和近30名本科生以合作作者的身份发表了研究论文，并成功找到了专业岗位。

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.