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Scientific Report 2004


Chemistry




Organic, Materials, and Analytical Chemistry


M.G. Finn, W.G. Lewis, J. Meng, D. Dìaz, S. Punna, V. Rodionov

In addition to synthetic chemistry research on viruses, our program encompasses organic, organometallic, and analytical chemistry. Special emphasis is placed on methods of chemical synthesis, the discovery of functional molecules, and catalysis.

Chip-based Mass Spectrometry of Small Molecules

In collaboration with G. Siuzdak and the Mass Spectrometry Laboratory at Scripps Research, we are developing the technique termed desorption/ionization on silicon (DIOS) for small-molecule analysis via matrix-assisted laser desorption/ionization instrumentation. Currently, we are tailoring the porous silicon platform for advanced applications. A good example is a new method for affinity purification and mass analysis that uses chemically functionalized porous silicon plates (Fig. 1).

Fig 1. Affinity purification on DIOS plates.

In this method, a protein is covalently labeled in solution with a probe molecule that bears a stable azide group (step 1) and is then digested into its component peptides (step 2). The resulting mixture of peptides is coupled with a biotinylated linker bearing an alkyne unit; only the peptides bearing an azide group are attached to the linker (step 3). The coupling reaction is the highly selective azide-alkyne cycloaddition. Last, the mixture is deposited on a porous silicon chip that has been covalently modified with biotin and coated with avidin (step 4).

When the chip is vigorously washed, all the peptides are removed except those bearing the biotinylated linker. The laser pulse of the mass spectrometer induces an efficient cleavage of the linker, detaching the adhered peptides in the DIOS analysis. This method can be used to identify the sites of reaction of enzyme inhibitors or to screen new compounds that may be inhibitors.

Synthesis And Use Of Formamidine Compounds

This past year, we continued our studies on the biologically active and chemically interesting formamidines. Our modular synthesis of formamidine ureas enabled us to make a large series of these compounds and study their reactivity. We also extended our synthetic efforts to the development of a reliable synthesis of parent formamidine compounds, which are far more stable than urea derivatives and occur in many other compounds that may be useful as pharmaceutical agents.

The rates of hydrolysis in aqueous solution of the full range of these formamidine compounds vary more than 100,000-fold, depending on the substituents. Furthermore, we found that formamidine ureas engage in 3 distinct modes of reactivity when presented with different biologically related nucleophiles. This versatile chemistry is being exploited in the design and testing of enzyme inhibitors. Preliminary results indicate that certain formamidines and formamidine ureas are reversible, high-affinity binders to acetylcholine-binding proteins, an important family of neurologic receptors.

Catalysis and Polymer Synthesis

In collaboration with K.B. Sharpless, V. Fokin, and H. Kolb, Department of Chemistry, we used highly reliable “click reactions” to create biologically active compounds. We also used the aforementioned copper-catalyzed cycloaddition of azides and alkynes to create novel functional polymers. Recent developments include the discovery of chemically stable materials that expand and contract in response to exposure to environmental stimulus. We also synthesized polymeric chains of biologically active compounds, such as carbohydrates with a single azide or alkyne group at the end of the chain, and attached these units to proteins, polymers, and surfaces.

Supporting these applications was the discovery of a potent new family of catalysts for the azide-alkyne reaction in which we used a sensitive method for screening reactions under dilute conditions (Fig. 2). In the best case, we improved the activity of the copper catalyst 50-fold, making this reaction the best one available for joining 2 reagents present in low concentrations. Our investigations of the mechanism of the process provided insights that resulted in further refinement of the design of catalysts.

Fig. 2. Fluorescence-based screen for catalysts of the azide-alkyne cycloaddition reaction. The plate at the bottom shows the identification of 2 new active catalysts (white boxes).

Publications

Dìaz, D.D., Finn, M.G. Expanded chemistry of formamidine ureas. Org. Lett. 6:43, 2004.

Dìaz, D.D., Finn, M.G. Formamidine ureas as tunable electrophiles. Chemistry 10:303, 2004.

Dìaz, D.D., Punna, S., Holzer, P., McPherson, A.K., Sharpless, K.B., Fokin, V.V., Finn, M.G. Click chemistry in materials synthesis, I: adhesive polymers from copper-catalyzed azide-alkyne cycloaddition. J. Polym. Sci. A Polym. Chem., in press.

Meng, J.C., Averbuj, C., Lewis, W.G., Siuzdak, G., Finn, M.G. Cleavable linkers for porous silicon-based mass spectrometry. Angew. Chem. Int. Ed. 43:1255, 2004.

Meunier, S., Strable, E., Finn, M.G. Crosslinking of and coupling to viral capsid proteins by tyrosine oxidation. Chem. Biol. 11:319, 2004.

Punna, S., Finn, M.G. A convenient colorimetric test for aliphatic azides. Synlett 99, 2004, Issue 1.

Raja, K.S., Wang, Q., Finn, M.G. Icosahedral virus particles as polyvalent carbohydrate display platforms. Chembiochem 4:1348, 2003.

Shen, Z., Go, E.P., Gamez, A., Apon, J.V., Fokin, V., Greig, M., Ventura, M., Crowell, J.E., Blixt, O., Paulson, J.C., Stevens, R.C., Finn, M.G., Siuzdak, G. A mass spectrometry plate reader: monitoring enzyme activity and inhibition with a desorption/ionization on silicon (DIOS) platform. Chembiochem, in press.

Smith, J.C., Lee, K.-B., Wang, Q., Finn, M.G., Johnson, J.E., Mrksich, M., Mirkin, C.A. Nanopatterning the chemospecific immobilization of cowpea mosaic virus capsid. Nano Lett. 3:883, 2003.

Taylor, D.J., Wang, Q, Bothner, B., Natarajan, P., Finn, M.G., Johnson, J.E. Correlation of chemical reactivity of Nudaurelia capensis ω virus with a pH-induced conformational change. Chem. Commun. (Camb.) 2770, 2003, Issue 22.

 


M.G. Finn, Ph.D.
Associate Professor

Finn Web Site