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Scientific Report 2006
Chemistry
Organic, Materials, and Analytical Chemistry
M.G. Finn, J. Kuzelka, D. Prasuhn, S. Presolski, V. Rodionov, Y.-H. Lim, B. Venkataiah
In addition to synthetic chemistry research on viruses, our program encompasses organic, organometallic,
and materials chemistry. Special emphasis is placed on methods of chemical synthesis,
the discovery of functional molecules, and catalysis.
Mechanisms and Applications of Click Chemistry
The copper-catalyzed azide-alkyne cycloaddition
reaction, discovered in 2002 by V.V. Fokin and K.B. Sharpless, Department of
Chemistry, has been adopted by chemists all over the world for organic synthesis,
drug development, and materials science. We have continued our mechanistic studies
of the reaction and our efforts to apply the reaction to the synthesis of biologically
active compounds, materials, and bioconjugates.
A protocol for using the reaction in
the polyvalent decoration of scaffolds has been optimized (Fig. 1). In the most
demanding situations, with sensitive proteins at micromolar concentrations, the
use of sulfonated bathophenanthroline (compound 1 in Fig. 1) is vital. We
continue to develop new catalysts to remove the last barrier to convenient application
of the method, the need to perform the reaction in an inert atmosphere when protein
instability prevents the simultaneous use of a reducing agent. In addition, a variation
of the standard copper-catalyzed process has been uncovered in which aromatic
azides react with alkynes to give the 1,5-triazole isomer rather than the customary
1,4-triazole. Last, mechanistic studies have revealed changes in the rate-limiting
steps when certain copper-binding ligands and substrates are used.
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| Fig. 1. Bioconjugation
of alkynes to polyvalent azides via the copper complex of bathophenanthroline ligand. |
Synthesis and Use of Formamidine Compounds
We synthesized amidines, including formamidines
and formamidine ureas, and tested them for binding to the acetylcholine-binding
proteins of Lymnaea stagnalis and Aplysia californica, soluble homologs
of the nicotinic acetylcholine receptor. Compounds 2, 3, and 4
(Fig. 2) have moderate to high affinities for the target proteins, representing
a new class of receptor ligands. Whereas amidines such as compound 4 are
relatively stable, formamidine ureas such as compounds 2 and 3 are
deactivated during a period of approximately 1 hour by hydrolysis when not bound.
Using fluorescence spectroscopy and x-ray crystallography, we showed that the bound
molecules reside in the canonical hydrophobic pocket. Electrophysiologic measurements
indicated that compound 4 is a nicotinic receptor agonist, consistent with
its observed binding behavior. We are extending this research to molecules specific
for subtypes of the nicotinic receptor family. These studies are conducted in collaboration
with P. Taylor, University of California, San Diego, and A. Markou, Molecular and
Integrative Neurosciences Department.
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| Fig. 2. Amidine derivatives that bind to nicotinic receptor proteins. |
Publications
Dìaz, D.D., Converso, A., Sharpless,
K.B., Finn, M.G. 2,6-Dichloro-9-thiabicyclo[3.3.1]nonane:
multigram display of azides and cyanides components on a versatile scaffold. Molecules
11:212, 2006.
Dìaz, D.D., Finn, M.G. Facile synthesis of N,N′-bis[formamidine]ureas
and symmetrical N,N′-dsubstituted formamidines. Lett. Org. Chem. 2:621, 2005.
Dìaz, D.D., Finn, M.G., Mishima, M. Substituent effects on the gas-phase basicity of formamidine ureas. Eur. J. Org. Chem. 235, 2006, Issue
1.
Dìaz, D.D., Lewis, W.G., Finn, M.G. Acid-mediated amine exchange of N,N-dimethylformamidines: preparation of electron-rich formamidines. Synlett
2214, 2005, Issue 14.
Dìaz, D.D., Lewis, W.G., Finn, M.G. Activation of urea as a leaving group in substitution reactions of formamidine ureas. Chem. Lett. 34:78,
2005.
Dìaz, D.D., Rajagopal, K., Strable, E., Schneider, J., Finn, M.G. “Click” chemistry in a supramolecular environment: stabilization of organogels
by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. J. Am. Chem. Soc. 128:6056, 2006.
Dìaz, D.D., Ripka, A.S., Finn, M.G. 1-(tert-Butyl-imino-methyl)-1,3-dimethyl-urea hydrochloride. Org. Synth. 82:59, 2005.
Johnson, J.A., Lewis, D.R., Dìaz, D.D., Finn, M.G., Koberstein, J.T., Turro, N.J. Synthesis of degradable model networks via ATRP and click chemistry. J. Am. Chem. Soc. 128:6564,
2006.
Meng, J., Fokin, V.V., Finn, M.G. Kinetic resolution by copper-catalyzed azide-alkyne cycloaddition. Tetrahedron Lett. 46:4543, 2005.
Punna, S., Kaltgrad, E., Finn, M.G. “Clickable” agarose for affinity chromatography. Bioconjug. Chem. 16:1536,
2005.
Punna, S., Meunier, S., Sen Gupta, S., Venkataiah, B., Truong, P., McGavern, D., Finn, M.G. Polyvalent inhibition of the LFA-ICAM interaction. J. Am. Chem. Soc., in press.
Rae, C.S., Khor, I.W., Wang, Q., Destito, G., Gonzalez, M.J., Singh, P.R., Thomas, D.M., Estrada, M.N., Powell, E., Finn, M.G., Manchester, M. Systemic
trafficking of plant virus nanoparticles in mice via the oral route. Virology 343:224,
2005.
Sen Gupta, S., Kuzelka, J., Singh, P., Lewis, W.G., Manchester, M., Finn, M.G. Accelerated bioorthogonal conjugation: a practical method for the ligation of diverse functional
molecules to a polyvalent virus scaffold. Bioconjug. Chem. 16:1572, 2005.
Sen Gupta, S., Raja, K.S., Kaltgrad, E., Strable, E., Finn, M.G. Virus-glycopolymer conjugates by copper(I) catalysis of atom transfer radical polymerization and azide-alkyne
cycloaddition. Chem. Commun. (Camb.) 4315, 2005, Issue 34.
Whiting, M., Muldoon, J., Lin, Y.-C., Silverman, S.M., Lindstrom, W., Olson, A.J., Kolb, H.C., Finn, M.G., Sharpless, K.B., Elder, J.H., Fokin, V.V.
Inhibitors of HIV-1 protease via in situ click chemistry. Angew. Chem. Int. Ed. 45:1435, 2006.
Wu, P., Malkoch, M., Hunt, J.N., Vestberg, R., Kaltgrad, E., Finn, M.G., Fokin, V.V., Sharpless, K.B., Hawker, C.J. Multivalent, bifunctional dendrimers prepared by click chemistry. Chem. Commun.
(Camb.) 5775, 2005, Issue 46.
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