Sharpless, Karl Barry - The Scripps Research Institute

研究领域

Designing Man-Made Catalysts The Sharpless Lab pursues useful new reactivity and general methods for selectively controlling chemical reactions. Though the focus has progressed from regio- to stereo- to asymmetric and, now, to connectivity control, the core chemistry remains unchanged: the oxidation of olefins, that single most versatile, powerful and reliable (KBS argues) chemical transformation. The Sharpless Lab was the first academic chemistry group with robotics, and the lesson from the combinatorial numbers game was the primacy of reliability. "Click" chemistry was the Sharpless Lab's response: a set of powerful, virtually 100% reliable, selective reactions for the rapid synthesis of new compounds via heteroatom links (C-X-C). Click chemistry is integral now to all research within the Sharpless Lab. In 2002, the Sharpless group discovered CuAAC (the copper-catalyzed azide-alkyne cycloaddition), now known as a quintessential “click chemistry”. Recently the Sharpless group discovered SuFEx, another near-perfect click reaction. In concert with the thiol-ene reaction, these three make click chemistry a far-reaching method for drug discovery, chemical biology and materials science.

近期论文

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J. Dong, L. Krasnova, M.G. Finn, and K.B. Sharpless, Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry, Angew Chem Int Ed Engl, 53 (36), 9430-48 (2014). J. Dong, K.B. Sharpless, L. Kwisnek, J.S. Oakdale, and V.V. Fokin, SuFEx-Based Synthesis of Polysulfates, Angew Chem Int Ed Engl, 53 (36), 9466-70 (2014). R. K. Sit, V. V. Fokin, G. Amitai, K. B. Sharpless, P. Taylor, and Z. Radic, Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification, J Med Chem, 57 (4), 1378-1389 (2014). G. M. Morris, L. G. Green, Z. Radic, P. Taylor, K. B. Sharpless, A. J. Olson, and F. Grynszpan, Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase, J Chem Inf Model, 53 (4), 898-906 (2013). Y. Miyamoto, J. Kalisiak, K. Korthals, T. Lauwaet, D. Y. Cheung, R. Lozano, E. R. Cobo, P. Upcroft, J. A. Upcroft, D. E. Berg, F. D. Gillin, V. V. Fokin, K. B. Sharpless, and L. Eckmann, Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity, Proc Natl Acad Sci U S A, 110 (43), 17564-17569 (2013). T. Hirose, N. Maita, H. Gouda, J. Koseki, T. Yamamoto, A. Sugawara, H. Nakano, S. Hirono, K. Shiomi, T. Watanabe, H. Taniguchi, K. B. Sharpless, S. Omura, and T. Sunazuka, Observation of the controlled assembly of preclick components in the in situ click chemistry generation of a chitinase inhibitor, Proc Natl Acad Sci U S A, 110 (40), 15892-15897 (2013). N. P. Grimster, S. Connelly, A. Baranczak, J. Dong, L. B. Krasnova, K. B. Sharpless, E. T. Powers, I. A. Wilson, and J. W. Kelly, Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate, J Am Chem Soc, 135 (15), 5656-5668 (2013). J. G. Yamauchi, K. Gomez, N. Grimster, M. Dufouil, A. Nemecz, J. R. Fotsing, K. Y. Ho, T. T. Talley, K. B. Sharpless, V. V. Fokin, and P. Taylor, Synthesis of selective agonists for the alpha7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates, Mol Pharmacol, 82 (4), 687-699 (2012). Z. Radic, R. K. Sit, Z. Kovarik, S. Berend, E. Garcia, L. Zhang, G. Amitai, C. Green, B. Radic, V. V. Fokin, K. B. Sharpless, and P. Taylor, Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases, J Biol Chem, 287 (15), 11798-11809 (2012). N. P. Grimster, B. Stump, J. R. Fotsing, T. Weide, T. T. Talley, J. G. Yamauchi, A. Nemecz, C. Kim, K. Y. Ho, K. B. Sharpless, P. Taylor, and V. V. Fokin, Generation of candidate ligands for nicotinic acetylcholine receptors via in situ click chemistry with a soluble acetylcholine binding protein template, J Am Chem Soc, 134 (15), 6732-6740 (2012). R. K. Sit, Z. Radic, V. Gerardi, L. Zhang, E. Garcia, M. Katalinic, G. Amitai, Z. Kovarik, V. V. Fokin, K. B. Sharpless, and P. Taylor, New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases, J Biol Chem, 286 (22), 19422-19430 (2011). S. W. Millward, R. K. Henning, G. A. Kwong, S. Pitram, H. D. Agnew, K. M. Deyle, A. Nag, J. Hein, S. S. Lee, J. Lim, J. A. Pfeilsticker, K. B. Sharpless, and J. R. Heath, Iterative in situ click chemistry assembles a branched capture agent and allosteric inhibitor for Akt1, J Am Chem Soc, 133 (45), 18280-18288 (2011). P. Gastaminza, S. M. Pitram, M. Dreux, L. B. Krasnova, C. Whitten-Bauer, J. Dong, J. Chung, V. V. Fokin, K. B. Sharpless, and F. V. Chisari, Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection, J Virol, 85 (11), 5513-5523 (2011). R. Cochran, J. Kalisiak, T. Kucukkilinc, Z. Radic, E. Garcia, L. Zhang, K. Y. Ho, G. Amitai, Z. Kovarik, V. V. Fokin, K. B. Sharpless, and P. Taylor, Oxime-assisted acetylcholinesterase catalytic scavengers of organophosphates that resist aging, J Biol Chem, 286 (34), 29718-29724 (2011). T. Weide, S. A. Saldanha, D. Minond, T. P. Spicer, J. R. Fotsing, M. Spaargaren, J. M. Frere, C. Bebrone, K. B. Sharpless, P. S. Hodder, and V. V. Fokin, NH-1,2,3-Triazole-based Inhibitors of the VIM-2 Metallo-beta-Lactamase: Synthesis and Structure-Activity Studies, ACS Med Chem Lett, 1 (4), 150-154 (2010). Z. Radic, J. Kalisiak, V. V. Fokin, K. B. Sharpless, and P. Taylor, Interaction kinetics of oximes with native, phosphylated and aged human acetylcholinesterase, Chem Biol Interact, 187 (1-3), 163-166 (2010). R. Vanacore, A.-J. L. Ham, M. Voehler, C. R. Sanders, T. P. Conrads, T. D. Veenstra, K. B. Sharpless, P. E. Dawson and B. G. Hudson, A Sulfilimine Bond Identified in Collagen IV, Science, 325(5945), 1230 (2009). C. A. Valdez, J. C. Tripp, Y. Miyamoto, J. Kalisiak, P. Hruz, Y. S. Andersen, S. E. Brown, K. Kangas, L. V. Arzu, B. J. Davids, F. D. Gillin, J. A. Upcroft, P. Upcroft, V. V. Fokin, D. K. Smith, K. B. Sharpless and L. Eckmann, Synthesis and Electrochemistry of 2-Ethenyl and 2-Ethanyl Derivatives of 5-Nitroimidazole and Antimicrobial Activity against Giardia lamblia, J. Med. Chem., 52(13), 4038 (2009). D. Minond, S. A. Saldanha, P. Subramaniam, M. Spaargaren, T. Spicer, J. R. Fotsing, T. Weide, V. V. Fokin, K. B. Sharpless, M. Galleni, C. Bebrone, P. Lassaux and P. Hodder, Inhibitors of VIM-2 by Screening Pharmacologically Active and Click-Chemistry Compound Libraries, Bioorg. Med. Chem., 17(14), 5027 (2009). J. Kalisiak, S. A. Trauger, E. Kalisiak, H. Morita, V. V. Fokin, M. W. W. Adams, K. B. Sharpless and G. Siuzdak, Identification of a New Endogenous Metabolite and the Characterization of Its Protein Interactions through an Immobilization Approach, J. Am. Chem. Soc., 131(1), 378 (2009).