Research Abstracts - 2007
Alex Barksdale - University of North Texas
Copper Schiff Base Complexes with Unusual Metal-like Properties
Rachel Allenbaugh, Linda Doerrer
Department of Chemistry, Boston University
The Doerrer group is interested in the synthesis and conduction properties of low-dimensional systems. A few copper Schiff base complexes in the literature exhibit peculiar visual properties, namely vibrant colors, reminiscent of the colors of metallic, conducting substances including organic superconductors such as Cu phthalocyanine. It was proposed that RIXS (resonant inelastic x-ray scattering) be used to measure the electronic structure of these materials in the solid state and thereby characterize their apparent conducting behavior. RIXS samples are deposited in high vacuum and therefore volatile Cu species were desired. In general, fluorinated compounds sublime more readily which facilitates vapor deposition for x-ray scattering experiments. Following a facile route to the synthesis of metallated salen complexes from the reaction of salicylaldehyde, diamines, and metal acetate, we were able to easily synthesize our copper complexes. The synthesis of Cu(sal)2(DACH), a non-fluorinated and previously synthesized complex, as well as Cu(sal)2(CF3phen), a novel, fluorinated complex will be presented. Future studies on these compounds will include the analysis of intermolecular electronic structure by RIXS spectroscopy at the Brookhaven National Laboratory in collaboration with Professor Kevin Smith's group at Boston University, which could elucidate the mystery of their spectacular colors.
Timothy Berkelbach - New York University
An adaptive step-size algorithm for the determination of free energy differences via the Jarzynski pulling method
Gerrick Lindberg, Feng Wang
Department of Chemistry, Boston University
The free energy difference, ?F, which determines the direction and extent of a reaction, is extremely important throughout chemistry. To estimate the free energy difference with the Jarzynski method, one first calculates the work performed in ‘pulling’ a system from one state to another. Although the second law of thermodynamics dictates that the average work performed in an ensemble of such pullings provides an upper bound to ?F, i.e. áWñ ≥ ?F, Jarzynski’s theorem identically relates the work performed and the free energy difference: áexp(-W/kT)ñ = exp(-?F/kT). This result remarkably holds for any arbitrary pulling speed. Unfortunately, the number of pullings required for good statistics grows exponentially as the pulling speed increases. Herein, we introduce an adaptive step-size method, which varies a pulling parameter l so that a pre-specified amount of work is performed with each step. Such a scheme takes smaller steps when each step does a large amount of work, but takes larger steps when each step only performs a small amount of work, making this technique more efficient than standard approaches where the step size is constant. To demonstrate the efficiency of this approach, calculations are carried out to address three test problems: determining the free energy difference of classical harmonic oscillators (Einstein crystals) with different force constants, determining the free energy difference between van der Waals gases at different pressures, and determining the excess free energy of TIP4P water.
Chuan-Xing Ho - Denison University
Development of a microfluidics platform to facilitate multidimensional screening
John R. Goodell, Aaron B. Beeler, John A. Porco, Jr.
Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University
Discovery of novel chemotypes and methodologies with potential pharmaceutical or industrial applications has benefited from multidimensional reaction screening strategies. To facilitate this screening approach, a microfluidic platform was developed to improve reaction screening efficiency by offering more reliable control of reaction conditions as compared to traditional screening methods. In this project, preliminary flow experiments were conducted to optimize system parameters for various reaction times and solvents. Using the optimized system parameters, exploratory experiments were conducted to prepare for a reaction screen involving a retro-Dieckmann-type ring-opening on 3-methoxy-6-methyl-7- phenylbicyclo[3.2.1] oct-3-ene-2,8-dione. As part of this exploratory investigation, a small selection of heteroatom nucleophiles and non-nucleophilic bases were screened using the microfluidic platform. Results suggest that the bicyclo-dione substrate reacts with benzyl amine to afford the ring opened product in 5 minutes at 30 ?C in the presence of diazabicycloundec-7-ene. Based on these findings, future work will entail performing the full proposed multidimensional reaction screen on the microfluidic platform.
Dion Jacobs - University of the Virgin Islands
Understanding the Chemical Basis of the Genetic Disease Phenylketonuria (PKU)
Breia Lewis, Gulbenk Anarat, John Caradonna
Department of Chemistry, Boston University
Our research centers on trying to understand the structure of the enzyme phenylalanine hydroxylase (PAH). PAH is the enzyme responsible for causing the essential amino acid phenylalanine to covert to tyrosine, another amino acid. PAH uses a cofactor tetrahydrobiopterin and molecular oxygen to catalyze this reaction. Malfunctions of the enzyme leads to a condition known as phenylketonouria (PKU), a genetic disorder which symptoms include extraneous amounts of phenylalanine within the blood stream and mental retardation. Truncated crystal structures of PAH have been determined. However, structures of wild-type PAH have yet to be determined. These structures would strengthen knowledge in regards to where a mutation could occur on the enzyme and possible factors causing the mutation. Additionally, the crystallization of PKU mutants could be used in comparisons to the crystal structures of the truncated enzyme to further understand the dynamics of the enzyme. The different forms of the enzymes that we wish to study have been expressed in E. Coli cells and purified by ammonium sulfate precipitation and ionic exchange chromatography techniques. The purified enzyme was then tested for purity using SDS-Gel electrophoresis analysis prior to crystallization.
Joyce Lee - Loyola Marymount University
Analyzing Intramolecular Proton Transfer in Malonaldehyde
Yann Tambouret and David Coker
Department of Chemistry, Boston University
The theory of quantum mechanics is applied when analyzing the tunneling dynamics present in malonaldehyde. The potential energy surface (PES) of malonaldehyde is characterized when the compound undergoes an intramolecular hydrogen atom transfer between the two oxygen atoms. A program which involves solving the velocity verlet algorithm is constructed and consists of two in-plane proton coordinates, x and q. These two coordinates represent the position/velocity of the proton and the origin is defined at the energy barrier of the PES. The coordinate Hx, which represents the actual movement of the proton, is coupled to the Hq coordinate, the harmonic vibrations within the bonds and angles. Contour plots of the PES show a double-well potential of a rigid molecule (excluding Hx and Hy) coupled to a harmonic oscillator. In the classical standpoint, the motion of the particle is dependent on one velocity at a specific point. In quantum mechanics, the particle exhibits a wavelike behavior and its wavefunction describes the particle being in many positions/velocities. The wavefunction describing the particle can penetrate through the barrier and extend to the other side of the potential energy surface. The geometries of the structures were established by using Gaussian under the following conditions: Restricted Hartree Fock (RHF) method, 6-31G* basis set. Multiconfiguration Time Dependent Hartree (MCTDH) calculations have been carried out to determine the motion of a particle through quantum dynamics. This involves integrating the time-dependent Schroedinger equation in order to determine the wavefunction at a later time.
Ben Michelson - Keene State College
Studies directed towards the total synthesis of (-)-dictyostatin
Frauke Pohlki and Jim Panek
Department of Chemistry, Boston University
Many marine organisms prove to be rich sources of compounds that possess anticancer properties. Dictyostatin is a compound that was isolated by GR Pettit initially in 1994 from mass quantities of the dark marine spongia sp. (order Dictyoceratida, class Demospongiae, family Spongiidae) collected in the Maldives islands in 1986 and 1988, then isolated again from the Lithistida sponge, family Corallistidae, by I Paterson and AE Wright and complete structure determined in 2003 using specimens collected off the north coast of Jamaica. Dictyostatin is highly cytotoxic in two paclitaxel resistant cancer cell lines. Currently, total syntheses have been published by I Paterson in 2004, DP Curran in 2004, AJ Phillips in 2006, and PV Ramachandran in 2007. The discovery of a novel total synthesis would facilitate drug optimization and development of dictyostatin. Our studies are directed toward a synthesis using a common homoallylic alcohol precursor for two out of the three building block fragments in the retrosynthesis and employing a ring closing alkyne metathesis (RCAM) to form one of the (Z)- double bonds of the macrolactone. The common homoallylic alcohol precursor is derived from highly enantioenriched (E)-crotylsilanes synthesized by using a double-stereodifferentiating crotylation reaction. Four possible catalysts are being studied for use in the RCAM.
Meghan Nines - Lock Haven University of Pennsylvania
Developing a library of flavivirus human pathogen inhibitors via inverse electron demand Diels-Alder cycloaddition reactions
Zhiyuann Ma, John Snyder
Department of Chemistry, Boston University
Currently, no drugs are available to treat flaviviruses, such as West Nile Virus, Japanese Encephalitis, and Dengue Fever. The goal of the project is to synthesize a lead drug candidate with antiviral activity at a nanomolar concentration. This will be achieved by varying the substituents at various positions on a lead compound that was found to be active at the micromolar scale. The lead compound belongs to a class of compounds known as pyridazinoindoles (3), which are produced via an inverse electron demand Diels-Alder (IEDDA) reaction between 3,6-dicarbomethoxy-1,2,4,5-tetrazine (1) and indole (2). To create an active antiviral compound (5), the pyridazinoindole must undergo an amidation reaction, and the catalyst trimethyl aluminum was found to be effective at specifically targeting one ester for amidation. The library of compounds to be tested for antiviral screening is formed by varying the amines used for amidation (4) as well as the substituents on the aromatic ring of the pyridazinoindole (X). Also, the antiviral activities of amides created from imidazopyridazine are being investigated. Imidazopyridazine is synthesized using an IEDDA reaction between tetrazine and imidazole. Further chemistry is being explored involving the N-methylpropargyl amide. The copper-catalyzed azide-alkyne cycloaddition “click” reaction is being applied to the triple bond of this amide to create a triazole, which could have interesting antiviral attributes. So far, two compounds have been found to have improved activity over the original compound, and the results of the antiviral activity screening of the latest set of compounds are expected shortly.
Ilyssa Ramos - East Stroudsburg University
Determining the Solvent Accessible Surface of DNA via Hydroxyl Radical Cleavage Reaction
Steven Parker and Thomas D. Tullius
The hydroxyl radical (.OH) is a highly reactive free radical that can cleave nucleic acids, generating distinct and reproducible cleavage patterns. In the Tullius lab the hydroxyl radical has been used to generate detailed maps of DNA structure. The hydroxyl radical attacks DNA by abstracting a hydrogen atom located within the deoxyribose sugar of the DNA backbone. Previous studies based on the Deuterium Kinetic Isotope Effect have elucidated that the extent of cleavage is based on the accessibility of the hydrogen atoms of the deoxyribose to the solvent. Therefore, the hydroxyl radical can be used as a probe of DNA solvent accessibility, an important structural feature. Data collected from multiple cleavage experiments have been used to generate the .OH Radical Cleavage Intensity Database (ORChID). The ORChID database has been used to develop a prediction algorithm that can predict the hydroxyl radical cleavage pattern of a DNA sequence of any length with significant accuracy. In order to expand the ORChID database a new sequencing instrument, the CEQ8000 has been acquired. To make use of the new instrument, the conditions under which it is run must be optimized. Good results from the CEQ8000 can only be obtained if the noise in the sample is reduced to a minimum. In order to do this it is necessary to optimize the purification of a PCR product and the products of the subsequent hydroxyl radical cleavage reactions. The experimental results can be used in the expansion of the ORChID database consequently increasing the validity of the cleavage prediction algorithm.
Elizabeth Smothers
Alteration of Amino Acid Residues in the Conserved Motif of Archael Thioredoxin
Sanghamitra Mitra and Sean J. Elliott
Thioredoxin (Trx) belongs to a superfamily of proteins containing a redox-active disulfide bond. The primary function of Trx is to maintain the reducing atmosphere in the cytoplasm of the cell. Trx’s exhibit a strictly conserved motif consisting of a -CXXC- amino acid sequence. It has been suggested that the alteration of the variable amino acid residues in the conserved motif can alter the redox properties of Trx. The goal of this project was to generate a series of Trx variants containing one of either the acidic amino acids, glutamic acid and aspartic acid, or the basic amino acids, lysine and arginine, at the first variable amino acid residue within the conserved motif. A recombinant archael Trx was selected as a template. As a control, a variant with amino acid residues similar in the conserved motif to the prototypical Escherichia coli Trx has also been generated. Each of the variants has been successfully generated by site-directed mutagenesis. To date, two of the five variants have been successfully over-expressed and purified, and we are in the process of obtaining the other three.
