RUI: Synthesis and Study of Carbohydrate Processing Enzyme Inhibitors (Polyhydroxylated Pyrrolidines, Pyrrolizidines and Indolizidines)

本项目涉及碳水化合物加工酶的潜在小分子抑制剂的合成、计算机建模和酶学研究。一个通用的，有效的不对称合成，从商业上可用的糖开始，将开发一个多羟基吡咯烷，吡咯烷和吲哚嘧啶家族的每一个立体异构体，其中一些已知会抑制碳水化合物加工酶。虽然这类羟基化生物碱已经被发现很长时间了，但并不是每一类化合物的每一种可能的立体异构体都被研究过。这三类化合物的合成的核心是一锅还原开环/还原胺化反应，该反应从6-卤代吡喃苷还原为取代的5-己烯醛开始。然后在相同的反应混合物中，5-己烯醛被还原胺化形成取代的6-氨基-1-烯烃。在吡咯烷的情况下，6-氨基-1-烯烃立即发生分子内亲核取代反应，形成取代的2-乙烯基吡咯烷。如果在还原性胺化反应中使用的胺被适当取代，则在内部亲核取代之前，通过钌催化的甲基化反应可以合成吲哚吡啶和吡咯利嗪体系。所得到的多羟基生物碱将被测试其抑制碳水化合物加工酶的能力。抑制结果将与计算机建模和对接研究相结合，以建立预测这些生物碱的哪些立体异构体应该抑制特定糖苷酶的标准。有了这个RUI奖，有机和大分子化学项目支持斯通希尔学院化学系的Louis J. Liotta教授和普罗维登斯学院化学和生物化学系的Kenneth R. overre教授的研究。碳水化合物是地球上分布最广泛的天然有机化合物。该项目将提供新的合成方法和对碳水化合物加工酶性质的新见解。结合建模和对接研究，本提案能够获得生物碱的每一个立体异构体，这将允许对碳水化合物加工酶的结构/功能关系进行更深入的研究。这种结构/功能关系的研究将导致对许多重要生物过程的更好的分子理解，并可能导致设计更好的抑制剂，最终导致更大的成功药物开发的机会。该项目将由一群不同的本科生进行，每年夏天还将包括两名经济困难的高中生和一名高中教师。

This project addresses the synthesis, computer modeling, and enzymatic studies of potential small molecule inhibitors of carbohydrate-processing enzymes. A general, efficient asymmetric synthesis, starting from commercially-available sugars, will be developed for every stereoisomer of a family of polyhydroxylated pyrrolidines, pyrrolizidines and indolizidines, some of which are known to inhibit carbohydrate processing enzymes. Although these classes of hydroxylated alkaloids have been known for a long time, not every possible stereoisomer of the compounds within each class has been studied. Central to the syntheses of all three classes of compounds is a one-pot reductive ring opening/reductive amination reaction that starts with the reduction of a 6-halopyranoside to a substituted 5-hexenal. The aldehyde of 5-hexenal is then reductively aminated to form a substituted 6-amino-1-alkene in the same reaction mixture. In the case of the pyrrolidines, the 6-amino-1-alkene immediately undergoes an intramolecular nucleophilic substitution reaction to form substituted 2-vinyl-pyrrolidine. If the amine used in the reductive amination is properly substituted, both the indolizidines and pyrrolizidines systems can be synthesized by performing a ruthenium-catalyzed metatheses reaction before the internal nucleophilic substitution. The resulting polyhydroxylated alkaloids will be tested for their ability to inhibit carbohydrate-processing enzymes. The inhibition results will be coupled with computer modeling and docking studies to establish criteria for predicting which stereoisomers of these alkaloids should inhibit specific glycosidasesWith this RUI award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Louis J. Liotta, of the Department of Chemistry at Stonehill College, and Professor Kenneth R. Overly, of the Department of Chemistry and Biochemistry at Providence College. Carbohydrates are the most widely distributed, naturally occurring organic compounds on earth. This project will provide both new synthetic methodology and new insight into the nature of carbohydrate-processing enzymes. The ability to obtain every stereoisomer of the alkaloids in this proposal in conjunction with modeling and docking studies will allow for a more thorough study of the structure/function relationship of carbohydrate-processing enzymes. This study of structure/function relationships will lead to a better molecular understanding of many important biological processes and could lead to the design of better inhibitors, ultimately leading to a greater chance that successful drugs will be developed. The project will be carried out by a diverse group of undergraduate students and will also include two economically disadvantaged high school student collaborators and one high school teacher each summer.