Nitrosopurines En Route to Potently Cytotoxic Asmarines†
Kanny K. Wan
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Kotaro Iwasaki
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorJeffrey C. Umotoy
Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Prof. Dr. Dennis W. Wolan
Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Dennis W. Wolan, Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Ryan A. Shenvi, Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Prof. Dr. Ryan A. Shenvi
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Dennis W. Wolan, Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Ryan A. Shenvi, Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorKanny K. Wan
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Kotaro Iwasaki
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorJeffrey C. Umotoy
Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Prof. Dr. Dennis W. Wolan
Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Dennis W. Wolan, Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Ryan A. Shenvi, Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Prof. Dr. Ryan A. Shenvi
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Dennis W. Wolan, Department of Molecular and Experimental Medicine and Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Ryan A. Shenvi, Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
Search for more papers by this authorThis work was supported by the NIH (GM104180 and the NSF GRFP (K.K.W.; DGE-1346837). We thank Dr. C. E. Moore and Prof. A. L. Rheingold (UCSD) for X-ray crystallographic analysis. We thank TSRI, Eli Lilly, Boehringer Ingelheim, Amgen, the Baxter Foundation, and the Sloan Foundation for additional financial support.
Graphical Abstract
Unnatural product: A nitrosopurine ene reaction easily assembles the asmarine pharmacophore and transmits remote stereochemistry to the diazepine-purine heterocycle. This reaction generates potent cytotoxins which exceed the potency of asmarine A and supersede the metabolites as useful leads for biological discovery.
Abstract
A nitrosopurine ene reaction easily assembles the asmarine pharmacophore and transmits remote stereochemistry to the diazepine-purine hetereocycle. This reaction generates potent cytotoxins which exceed the potency of asmarine A (1.2 μM IC50) and supersede the metabolites as useful leads for biological discovery.
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