COBRE: UKS: CORE C: MEDICINAL CHEMISTRY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。注意：此信息在以前的报告中可以在Core D下找到。基于来自HTS实验室的hit， Core C支持了两个具有药物化学专业知识的项目，并制备了一些hit化合物的类似物。一个项目的重点是合成一个蛋氨酸氨基肽酶抑制剂库，作为潜在的抗癌、抗菌和抗真菌药物。该酶与取代呋喃酸共结晶，成为进一步研究的先导化合物。为了实现这一目标，我们开发了一种捕获-铃木释放策略来生成各种芳基取代呋喃和噻吩羧酸。目前的工作旨在优化相关吡啶羧酸的实验条件。此外，正在研究使用易组合-分类-裂解方法的iori Accutag¿协议，以生成上述联芳基化合物。第二个项目涉及MurA，一种细菌细胞壁合成酶。抑制该酶可产生抗菌活性。通过HTS鉴定了MurA抑制剂，并与酶共结晶。这些初步数据用于提交NIH RO3申请，并制定了结构-活性关系研究计划。继续购置大型合成设备和分析仪器，以增强Core C实验室的能力。核心C人员一直积极参与组建NIPTE（国家制药技术与教育研究所），该组织的目标是制造更安全、更便宜的药物，并保持美国在药品制造方面的优势。corec继续与corea合作组织专题讨论会、讲习班和研讨会。corec还为HTS实验室收购了化合物。我们预计在下一个财政年度启动1-2个新的药物化学项目。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Note: This information was found under Core D in previous reports. Based on hits from the HTS laboratory, Core C has supported two projects with medicinal chemistry expertise and has prepared a number of analogues of the hit compounds. One project focuses on the synthesis of a library of methionine amino peptidase inhibitors as potential anticancer, antibacterial, and antifungal agents. The enzyme was co-crystallized with a substituted furoic acid, which became the lead compound for further study. Towards this goal, we have developed a catch-Suzuki-release strategy to generate various aryl substituted furan and thiophene carboxylic acid. Current efforts are aimed at optimizing experimental conditions for related pyridine carboxylic acids. In addition, investigations using Irori Accutag¿ protocols for facile combine-sort-cleave methodology are being pursued for the generation of the aforementioned biaryl compounds. The second project concerns MurA, a bacterial cell wall synthesis enzyme. Inhibition of the enzyme leads to antibacterial activity. MurA inhibitors were identified by HTS and one hit compound was co-crystallized with the enzyme. These preliminary data were used to submit an NIH RO3 application and a plan for structure-activity relationship studies was developed. The acquisition of large-scale synthesis equipment and analytical instrumentation was continued to enhance the capabilities of the Core C laboratory. Core C personnel have been active participants in the formation of NIPTE (National Institute for Pharmaceutical Technology and Education), an organization that has as its goal making safer, cheaper drugs and to preserve the U.S. advantage in drug manufacturing. Core C continued to organize symposia, workshops and seminars in collaboration with Core A. Core C also and made acquisition of compounds for the HTS laboratory. We expect to initiate 1-2 new medicinal chemistry projects in the coming fiscal year.