GAP Chemistry Approaches to Chiral Amino Acids, Peptides and Peptidomimetics

描述(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；GAP化学表明，无需使用层析和结晶就可以实现氨基化合物的有机合成。这项eChem计划探索不对称合成一系列非天然氨基酸和-氨基膦酸酯的GAP化学，以服务于神经药物的设计和合成。GAP化学还有利于神经肽和一般多肽的合成以及多肽的仿生学，避免了传统的固相-多肽合成和溶液-多肽合成的缺点。尽管液相-多肽合成(LPPS)是一种杂化技术，但该方法仅适用于简单的酰胺键形成的多肽合成；其缺点是模板的相对分子质量极大，不便于大量生产；通过仔细控制固化/结晶条件，生成结晶前体和产物往往需要较长的周期(有时甚至需要一周)。相比之下，该项目的GAP化学工具将具有固相多肽合成(SPPS)、溶液多肽合成(SOPPS)和液态多肽合成(LPPS)的优势，包括通过过滤进行快速纯化，一个潜在的自动化手动选择(对于SPPS)；容易从mg扩大到Kg，并且不需要过多的试剂或昂贵的仪器(对于SoPPS和LPPS)。到目前为止，还没有一种有效的方法来实现不对称合成，然后再进行多肽合成。在这个eChem项目中，从GAP合成中得到的由N-膦和N-膦部分连接的特殊手性氨基酸可以用于设计和合成与药物滥用有关的重要靶标，如神经肽、N-花生四烯酰甘氨酸衍生物、N-花生四烯酰乙醇胺、血加压素和神经降压素类似物。PI的研究小组取得了可喜的初步结果，这使这一建议变得可行。在过去的14年里，该院培养了近60名本科生和18名毕业生(包括5名中国协作毕业生，其中1名是中国奥运化学金牌获得者)，从事有机和生物有机/医药研究。所有这些毕业生和近30名本科生都作为PI的合著者发表了研究论文，并成功找到了专业职位。 与公共健康相关：这项提案计划探索非天然氨基酸和氨基膦酸不对称合成的新策略，用于神经药物的设计和合成。GAP化学的新概念也被应用到神经肽和多肽的合成中，使这些合成对环境友好，而不需要繁琐的工作。GAP多肽的合成可以避免已有方法的缺点。在PI的实验室中取得了初步的结果，证明该方案是可行的。到目前为止，PI的团队已经培训了近60名本科生和18名毕业生进行有机/药物研究，其中包括一名中国奥运化学金牌得主。所有毕业生和近30名本科生都在PI发表了研究论文。所有这些学生要么成功进入医学院，要么在制药公司找到了工作。

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.