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Our summer research program is designed to match each student with a faculty member to optimize the research experience for all participants. The application form asks you to rank your top three preferences of projects. If you want more information about a specific project (for example what background you need and which techniques you will learn) please contact the faculty directly via e-mail. General inquiries may be directed to Prof. Linda Brunauer at firstname.lastname@example.org.
Analytical Chemistry: Suljak
The aim of the proposed project is to understand structural and packing anomalies in ultra submicron-sized oil droplets that are permanently encapsulated in thin polymer capsules. Confining the oil droplet affects various thermodynamic properties, such as enthalpies of phase transitions, transition temperatures, solubility and mixing behavior, and heat capacity.
Currently we have established the synthesis of poly(styrene) capsules that contain n-hexadecane (HD). In these capsules, the onset of the liquid-solid phase transition (17.1˚C for HD in bulk) is significantly shifted downwards (see Figure), whereas the solid-liquid phase transition is only slightly shifted downwards. The extent of this thermal hysterisis increases dramatically as the oil/polymer fraction is reduced. More interestingly, with repeated freeze-thaw cycles, the thermal hysterisis diminishes, indicating partial rupture, or ripening of the capsules. This rupturing depends strongly on the thickness of the capsule wall.
The continuation of this project will be further development of the polymer shell in order to avoid rupturing it, and variation of shell chemistry in order to further elucidate the hysterisis.
Tricyclic drugs long have been used in the treatment of various neurological imbalances. While much of the research in this area has been focused at the drug-receptor interface, it is important also to investigate drug interactions at the plasma membrane level, as it is necessary for these drugs to establish membrane interactions that favor their passage across membrane barriers, in order to accumulate in the nervous system in large enough quantities to elicit biological effects. Drug-membrane interactions can be divided into two categories: interactions promoting drug permeability, and interactions promoting drug retention (binding). Both types of interactions involve electrostatic interactions, though not much comprehensive data on either are available. In the proposed project the importance of membrane phospholipid composition in supporting the binding of a variety of tricyclic drugs will be examined. Model membrane bilayers of defined lipid composition will be generated by sonication. Binding of radioisotopically labeled imipramine and chlorpromazine to model membrane bilayers will be determined following separation of bound and unbound drug via centrifugal ultrafiltration; binding of other tricyclic drugs and their quaternary ammonium derivatives will be assessed by measurement of binding-linked increases in natural drug fluorescence. Experimental parameters (e.g., ionic strength, pH, lipid composition) will be varied in order to investigate the importance of electrostatic and hydrophobic interactions in drug-lipid binding. The impact of drug binding on the compositional integrity of the two leaflets of the plasma membrane will also be examined by measuring drug-linked alterations in the extractability of fluorescent and/or radiolabeled phospholipid derivatives from erythrocytes.
As part of a research program aimed at studying how attached molecules affect the structure and function of peptides, we have recently synthesized several novel aminooxy amino acids.1,2 After their incorporation into peptides, these amino acids reveal side chains that can be reacted chemoselectively with reducing sugars to generate neoglycopeptides (Fig. 1). Importantly, our neoglycopeptides maintain biological relevance to natural glycopeptides because the sugars remain in their cyclic conformations and are close to the peptide backbone. Moreover, our strategy allows the facile combining of many different sugars with any given peptide. As a result, with a small amount of synthesis, we can create large numbers of neoglycopeptides.
Student projects will involve the synthesis of neoglycopeptide arrays and the subsequent use of these arrays to address biological issues of structure and function. The synthesis of the arrays exposes students to (1) the organic synthesis of novel amino acids, (2) solid phase peptide synthesis, and (3) sugar/peptide conjugation reactions along with extensive use of the analytical techniques of nuclear magnetic resonance (NMR), high performance liquid chromatography (HPLC), and electrospray ionization mass spectrometry (ESI-MS). The arrays will be used to address how attached sugars protect peptides from proteolysis, how they affect secondary structure, and how they affect the thermostability of peptides and small proteins.
Fig. 1. A chemoselective reaction for synthesis of a neoglycopeptide. The aminooxy group reacts selectively with the sugar in the presence of many other functional groups.
Mild approaches for forming rings are of on-going interest in synthesis. Our interest in this context is the possibility of producing heterocycles by way of the N-H insertion reaction of a vinylidene derived from an aminoketone 1 as outlined below in a general way.
The vinylidene is available by treating the substrate with a diazophosphonate, (RO)2P(O)CHN2, and base, a transformation for which there is considerable precedent in our own work.3 Moreover, the key step in which the carbene effects the N-H insertions has precedent as well, at least on an intermolecular basis,4 and intramolecular ring-forming insertions, albeit examples involving the vinylidene and C-H bonds, are known.5
The projects available to REU students would include exploring the overall reaction for the formation of mono- and bicyclic heterocycles. In the former case, studies could include substrates 1 where x = 1–5 and R2 = CH3. For the latter, aminoketones 2 with x = 0–3, y = 1–4, and R1 = CH3 would be subjected to the transformation. Success in effecting the annulation would produce enamines that could be subjected to further transformations of interest.
We have a long-standing interest in reversible photoreactions, especially when the two directions involve different pathways. In halocarbon solvents this can lead to decomposition of the halocarbon, beginning with hydrogen abstraction by a photogenerated radical.
One example of this occurs in the photolysis of iron(III) chloride in chloroform.6 Upon absorbing blue or near-UV light, FeCl3 is reduced to FeCl2 by chlorine atom dissociation. The chlorine radical abstracts hydrogen from CHCl3, leaving CCl3, which reacts with O2 to make CCl3OO, which itself abstracts hydrogen from the solvent to make CCl3OOH, trichloromethylhydroperoxide. This is a good oxidizing agent, and it reoxidizes FeCl2 almost immediately. The eventual products from the chloroform decomposition are CO2 and HCl, while iron(III) is regenerated. This occurs with near-UV radiation (or sunlight) that chloroform does not itself absorb.
The tetrachloroaurate ion also causes photocatalytic degradation, though not by the same mechanism as described above (in the initial photoevent Cl2 appears to be produced rather than Cl). This degradation can be verified by following the production of HCl. Unlike FeCl3, AuCl4‾ can be dissolved in water without rapid hydrolysis, and photocatalytic chloroform degradation also occurs in CHCl3-saturated water. Although it is satisfying to carry out this homogeneous process, heterogeneous photocatalysis would obviously have greater potential utility.
We propose to investigate the photocatalytic degradation of CHCl3 by incorporating AuCl4‾ onto a solid support and exposing it to visible or near-UV radiation, first in neat chloroform and then in water with dissolved chloroform. Tetrachloroaurate is retained strongly by porous glass, silica gel, and anion exchange resins. Initially we will adsorb AuCl4ˉ onto a silica gel TLC plate, and immerse a portion of the plate in a cuvette with CHCl3 or H2O/CHCl3. This will provide good access to the illuminating radiation and to the solution. Additional substrates will be prepared for use in a similar fashion. Other complexes found to catalyze photodecomposition homogeneously will also be investigated.
We also propose examining photoreactions in bromoethane, including photocatalytic degradation reactions. Brominated hydrocarbons differ from chlorinated hydrocarbons in that hydrogen abstraction by Br is unfavorable. This limits the possibility of chain reactions, and makes complete degradation (to HBr and CO2) more difficult. Nevertheless, the formation of radical peroxy species in aerated solutions, one route to degradation, is still favorable. Dibromine is a product of direct or sensitized irradiation of brominated hydrocarbons, and an appropriate supported agent may be found to take up Br2, either by oxidative addition or by reduction and eventual formation of HBr.
HIV protease inhibition is an important pharmacological approach to combating the onset of AIDS in HIV infected patients. Two problems with this approach are the development of resistant mutant virons and the cost of producing the present commercial medications. Because many mutant virons are now present in HIV patients, continued development of novel HIV protease inhibitors is required. Furthermore, reducing the cost of preparing these drugs will allow for distribution of medications in the Third World, especially Africa, where HIV and AIDS infection has reached crisis proportions.
Abbott Laboratories has developed a highly effective class of HIV protease inhibitors (HIV PI's) utilizing a diaminohexandiol core, 1.7 Interestingly, many other HIV PI's utilize a similar core structure or a related diaminopentanol core.8 In contrast to the typical structures of HIV PI's, Wong has recently demonstrated that an amino pyruvic acid core, 2, produced a surprisingly effective inhibitor given the low molecular weight of the compound.9
To combine the effectiveness of the Abbott compounds, include the 1,2 dicarbonyl functionality described by Wong, and meet the requirements of economical synthesis, we have designed the core structures 3 and 4. In these molecules, R1, R2, R3 and R4 can be varied easily, and our initial synthetic targets have been the compounds where R1 = R2 = Z-valine and, in the case of 4, where R3 = R4 = phenyl.
Our approach to inhibitor 6 starts from the a-hydroxycarboxylic acid 5, which we have synthesized from phenylalanine using established literature procedures.10–12 Presently, the only two synthetic steps remain, deprotection and coupling with hydrazide 7. The synthesis of 8 from benzylhydrazine is accomplished easily from the intermediate 7 and was completed last summer as part of our REU program.
The synthesis of 8 has proven straightforward and we have prepared the core for 6 on gram-scale. In addition, the particular ease of synthesis of the oxamide core, 4, means it will be a valuable scaffold for further potential enzyme inhibitors. Presently, we are also preparing variations of 8 where we use new core structures linking two molecules of 7. Overall, the above scaffolds provide significant versatility in HIV PI design and synthesis. Most importantly, they provide a plethora of possible synthetic targets for undergraduate research projects that are achievable during the course of a summer.
Porphyrin assemblies have been used in heme protein models, artificial light-harvesting systems, catalytic scaffolds, and molecular devices.13 Most recently, self-assembling and covalently linked multiporphyrin systems have been of great interest in the development of nanomaterials.14 We seek to systematically investigate the spectroscopic and ligand-binding properties of several novel self-assembled and covalently linked porphyrin structures. The student projects will include an investigation of the dimerization of an imidazole-appended Zn(II) porphyrin using visible and NMR spectroscopy; 2) the characterization of the micelle formation of various derivatives of 5,10,15,20-(N-4-pyridiniumyl)porphyrin (T4PyP) and 5,10,15,20-(N-3-pyridiniumyl)porphyrin (T3PyP) including Zn(II), Co(II), and Fe(III) systems; and 3) structural characterization of two covalently-linked porphyrin dimer systems (Figure 1) and ligand-binding to Zn(II) derivatives.
The emergence of functional genomics has led to a growing need for analyzing protein molecules with an emphasis on their molecular variants (resulting from genetic polymorphisms or mutations) and post-translational modifications that determine the biological outcomes of changes at the genomic level. We are developing a simple, robust, and relatively inexpensive method for specifically detecting these protein variants. This approach couples the separation efficiency of capillary electrophoresis with the selectivity provided by aptamers, single-stranded oligonucleotides derived to bind to specific targets. Current efforts are focused on detecting variants of vascular endothelial growth factor (VEGF), a homodimeric glycoprotein implicated in tumor growth. Our objective is to develop aptamers that can specifically bind individual variants of VEGF with a particular phosphorylation or glycosylation site. Although more comprehensive approaches investigation protein variants and modifications are available (generally involving expensive instrumentation such as MALDI-TOF mass spectrometry), our work offers a more focused ability to study the implication of specific modifications. Successful development of a panel of aptamer probes will permit the ability to monitor the presence or increasing production of individual variants in a particular disease state.