The Sloan-Kettering Institute requests a dual 13C/1H CryoProbe (Cold Probe) to upgrade a 600 MHz NMR spectrometer. This instrumentation will be used by synthetic chemists who are developing new biological probes and therapeutic agents targeted to cancer, infectious diseases, and neurodegenerative disorders. Sloan-Kettering has a well-established and expanding chemistry program, but this instrumentation is not currently available to these chemists. The CryoProbe provides exceptionally high sensitivity (more than 4-fold higher than standard probe; more than 16-fold faster experiments), proton and carbon observation, and Z-gradients. The CryoProbe will provide significant new capabilities to these research teams, allowing rapid, routine, comprehensive analysis of (a) complex molecules available in only small quantities, such as natural product synthetic intermediates, carbohydrates, and peptidomimetics; and (b) large numbers of compounds synthesized during medicinal chemistry and combinatorial chemistry projects. In both cases, a full panel of otherwise time-consuming experiments can be performed (such as 13C-NMR, DEPT, J-RES, COSY, TOCSY, NOESY, ROESY, HMQC, HMBC, HETCOR), allowing complete structural identification and characterization. Previously inaccessible INADEQUATE experiments can also be considered. NIH-supported users include (1) Dr. Samuel Danishefsky, who is synthesizing natural products and glycopeptide vaccines with anti-tumor and anti-infective properties, several of which have been advanced to human clinical trials; (2) Dr. Gabriela Chiosis, who is developing modulators of the chaperones Hsp70 and Hsp90 to investigate their therapeutic potential; (3) Dr. Yueming Li, who is studying gamma-secretase function and inhibition to target Alzheimer's disease; (4) Dr. Bayard Clarkson, who is investigating kinase inhibitors as new treatments for chronic myeloid leukemia; (5) Dr. Derek Tan, who is developing diversity-oriented syntheses of natural product-based libraries for high-throughput screening against a broad range of biological targets and also developing new antibiotics targeting siderophore biosynthesis in pathogenic bacteria; (6) Dr. Steven Larson, who is developing new radiotracers for biochemical and metabolic studies to diagnose and treat cancer; and (7) Dr. Ouathek Ouerfelli, whose Organic Synthesis Core Facility provides chemistry services to more than 20 other NIH-supported investigators at Sloan-Kettering. The CryoProbe will be installed on a 600 MHz NMR spectrometer at the Sloan-Kettering Analytical NMR Core Facility, under the management of Dr. George Sukenick, who has 13 years of experience in directing this facility. ? ? Relevance: The requested instrumentation will be used by chemists at the Sloan-Kettering Institute to characterize synthetic molecules. Its extremely high sensitivity will greatly accelerate and assist their efforts to develop new biological tools and therapeutic agents to study and treat cancer, infectious diseases, and neurodegenerative disorders. ? ? ?
