COBRE: UKS: CORE C: MEDICINAL CHEMISTRY

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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.