COBRE: UKS: CORE C: MEDICINAL CHEMISTRY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 注：这一信息是在以前的报告核心D下找到的。 基于HTS实验室的HITS，Core C支持了两个具有药物化学专业知识的项目，并准备了许多HIT化合物的类似物。其中一个项目集中在合成蛋氨酸氨基肽酶抑制剂的文库，作为潜在的抗癌、抗菌和抗真菌药物。该酶与取代呋喃甲酸共结晶，成为进一步研究的先导化合物。为此，我们开发了一种捕捉-铃木释放策略来生成各种芳基取代的呋喃和噻吩羧酸。目前的工作主要是优化相关吡啶羧酸的实验条件。此外，正在进行使用irori Accutag方案的简易合并-分类-裂解方法的研究，以生成上述联芳化合物。第二个项目涉及细菌细胞壁合成酶Mura。抑制该酶会产生抗菌活性。用HTS鉴定了Mura抑制剂，其中一种HIT化合物与酶共结晶。这些初步数据被用来提交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，以加强核心C实验室的能力。C部门的核心人员一直是NIPTE(国家制药技术和教育研究所)的积极参与者，该组织的目标是制造更安全、更便宜的药物，并保持美国在药物制造方面的优势。Core C继续与Core A合作举办专题讨论会、讲习班和研讨会，并为高温超导实验室采购化合物。我们预计在下一财年将启动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.