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Chemistry 2007
Summer Science Research Abstract
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Synthesis of Model Molybdopterins
Lauren Dillon
Mentor: Professor Sharon Burgmayer
Molybdenum enzymes have important functions across life forms. The enzymes are involved in oxidation and reduction reactions. A lack of molybdenum enzymes can be very dangerous. The active site of the enzyme is known as the Molybdenum Cofactor (Moco). The cofactor consists of a dithiolene group substituted with a pterin moiety, known as molybdopterin, complexed with molybdenum. Attempts to isolate Moco have not been accomplished due its instability outside the enzyme. Therefore, Moco must be studied by building compounds modeled after it. The synthesizing of model Moco compounds has been a major focus of the Burgmayer lab.
A key to building the model is the synthesis of pterin compounds. A precursor of to the syntheses of different model molybdopterins is 6-chloropterin. Traditionally, 6-chloropterin has been made in the lab following a five step process. A disadvantage to this pathway is that the first step is costly and low yielding. This summer along with repeatedly completing this pathway, I will also test out a new proposed pathway. Most of the reactions of the pathway have been studied before. The reaction that will require the most attention is shown in Figure I. My goal for working with this new pathway is to improve its efficiency and the yields of its reactions.
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Structure and Function of Pterins through Molybdenum and Ruthenium Complexes
Belinda Leung
Mentor: Professor S. Burgmayer
Interest in pteridine chemistry is motivated by the interactions with transition metals. Pteridine complexes play a role in biological systems whether in enzymes or DNA. Resembling the transition metals, the pterin has the ability of conducting multi-electron redox reactivity which makes a complex of the pterin and transition metal behave unlike conventional complexes of the same formal oxidiation. This property issues a challenge for further investigation.
Professor Burgmayer’s research group has delved into two major areas of pteridine study. Molybdopterin, a dithiolene organic complex, coupled with molybdenum functions in enzymes which are employed in humans as well as metabolic reactions in plants and anaerobic respiration in bacteria. The lab is working to synthesize molybdeunum pterinyl-dithiolene complexes that mimic these cofactors. Due to the structure of pterins matching purines and pyrimidines of DNA, a look into DNA distortions by these molecules is warranted. Therefore, the group has also been synthesizing and studying various Ru(bpy)2(phenanthroline-pteridine) complexes as DNA intercalators.
Taking previously synthesized molybdenum and ruthenium complexes, I will be focused on crystallizing and characterizing their structures through X-ray crystallography. The determined structures will clarify the unique physical property of pterin-transition metal complexes. I will also be helping in the continuation of the synthesis of the Ru complexes and developing the synthesis of other transition metals with phenanthroline-pteridine ligands to study structural activity through hydrogen bonding.
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Molybdopterin Modeling and Investigation
Michelle Corder
Mentor: Professor Sharon
Burgmayer
A number of transition metals play an important role in the functioning and regulation of body processes. Almost all metals in the body are incorporated into the cofactors of enzymes where the reduction and oxidation processes at the metal centers control the behavior of the enzymes. Molybdenum, a typically neglected trace mineral is found in almost all organisms. The metal is imbedded into the cofactor of enzymes such as sulfite oxidase, xanthine oxidase, nitrate reductase in plants and bacteria, and DMSO reductase. Molybdenum enzymes are known to detoxify sulfites, a neurotoxin in the body, generate energy in the mitochondria, and regulate human growth. Molybdenum is also an important component of tooth enamel, and is suggested to play a role in the immune system and in sexual functioning of men.
All molybdenum enzymes contain a pterin ligand
coordinated to the molybdenum center via a dithiolene group,
more colloquially called molypdopterin (See Figure 1).
Recent studies have shown that there are a family of molybdenum
cofactors, nicknamed Moco. Although there has been a lot published
regarding molybdenum enzymes, there has been very little reported
regarding the role of the molybdopterin ligand. Our lab
aims to synthesize several Moco models and test the redox capability
of the models in order to better understand the redox activity
of the cofactor and the role of the pterin ligand. The synthetic
route consists of synthesizing the model ligand in the form
of an pterinyl or quinoxalyl alkyne and the precursor molybdenum
cofactor which is a tetrasulfide molybdenum complex (the pterinyl
alkynes are closer in structure to molybdopterin but the quinoxalyl
alkynes are easier to synthesize and therefore are used in preliminary
electrochemical testing of the models). My colleague, Lauren
Dillon, is preparing the pterinyl and quinoxalyl alkynes while
I have been currently working on the three-step synthesis of
the tetrasulfide precursor. The two molecules will be reacted
to make the Moco models in the reaction depicted in Figure
2 and Figure 3. All models are characterized
by NMR, FT-IR, UV-vis spectroscopy, ESI-MS and electrochemical
analysis will be conducted by cyclic voltammetry.
Figure 1. Molybdopterin
Figure 2. Synthetic route to Moco quinoxaline models.
Figure 3. Synthetic route to Moco pterin models.
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Investigation of DNA Intercalation by Ru(II)-bis(bipyridine)-Pteridinyl Complexes
Sanda Win
Mentor: Professor Sharon Burgmayer and Shannon Dalton
Intercalating molecules have potential as pharmaceuticals and probes of the replication machinery because intercalation distorts the helical shape of DNA, causing inhibition or replication enzymes, which can be useful for cancer treatment. Intercalation occurs when the planar aromatic ring of a molecule inserts itself between the base pairs of a DNA strand, resulting in a lengthening, stiffening and unwinding of the DNA double helix. In the area of DNA intercalation studies, transition metal intercalators have been a rich source of experimental date due to its redox and photophysical properties that make it possible to utilize multiple techniques to study DNA intercalation processes. The close structural similarity between nucleic acids and certain pteridines, particularly between guanine and pterin, suggests the possibility that C-pterin pair can mimic C-G hydrogen bonding. With this in mind, Ruthenium-polypyridyl complexes are studied. Previous studies have shown the ruthenium (II)-bis(bipyridine) complex of dipryidophenazine, [Ru(bpy)2(dppz)]2+, to have such intercalative capabilities.
During my summer research, I will continue to test intercalative capabilities of the ruthenium complexes designated [(bpy)2RuII(L)] where L stands for one of three variable pteridinyl-phenanthroline ligands is described. The three ligands, phenathroline-dimethylalloxazine, phenathroline-pterin and phenathroline-diaminopyrimidine were previously synthesized and characterized using 1H NMR, IR and ESI-MS. Each of the ligands was then reacted with Ru(bpy)2Cl2 to make the different [(bpy)2RuII(L)] complex, [(bpy)2RuII(L-Me2allox)](PF6)2, [(bpy) 2RuII(L-pterin)](PF6) 2 and [(bpy)2RuII(L-amino)](PF6)2. In addition, fluorescence spectroscopy, circular dichroism spectroscopy, plasmid unwinding gel electrophoresis, viscometry and thermal denaturation titrations will be used to investigate the interactions of these complexes with DNA.
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Exploring Molecular Moebius Strips
Melanie Edwalds
Mentor: Professor Michelle Francl
In recent years, the lines between the “distinct” fields of the various natural sciences (physics, chemistry, biology, geology, and mathematics) have become blurred. The increasing cooperation between the different fields has allowed some questions to be answered that perhaps previously seemed unanswerable. This summer I will be beginning my thesis research on molecular moebius strips, which I will be exploring from a quantum mechanical as well as a mathematical perspective.
In my research this summer I will be using a computer program called Gaussian 03 to find approximate solutions to the Schrödinger equation, which yields information about various physical properties of the molecule in question, such as the geometrical form of the molecule that corresponds to the lowest energy of the molecule. The molecules that I will be completing computations on are composed of between 15 and 30 benzene rings (or regular hexagons with carbon atoms at the vertices) and have the topological form of cylinders and moebius strips. The goal of the research is to determine the lowest energy geometry of the molecules. A comparison of the energies of the corresponding cylinders and moebius strips will allow us to determine what the addition of the half-twist costs energetically. These computations will be completed using at least two different computational models.
In addition to these computations, I will also begin attempting to figure out why the half-twist in a moebius band is localized, or in other words why the half twist is not distributed throughout the strip evenly. In order to do this I will first learn techniques in topology and differential geometry by reading textbooks on the subjects, including When Topology Meets Chemistry by Erica Flapan. One goal of this summer's research is to understand Erica Flapan's book, so that I can move forward when I continue this work throughout the next school year.
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Examining the Role of Photosensitizers in Hydrogen Gas Production
Amy Case
Mentor: Professor Jonas Goldsmith
Fossil fuels are limited resources that form CO2 when burned. Carbon dioxide acts as a greenhouse gas, contributing further to global warming. Hydrogen is an ideal alternative fuel. It is high energy and combusts to form water. This lab’s research focuses on harnessing the energy in sunlight to convert water into hydrogen gas.
This research will utilize a photosensitizer to activate an electron relay and produce hydrogen gas. A photosensitizer (in this case Ru(4-(5-thiopentyl)-2,2’-bipyridine)3 ) is a metal complex that will absorb the energy from sunlight and transfer it to the electron relay, another metal complex. The electron relay will react with the protons in water and make H2.
This summer I will attempt to synthesize 4-(5-thiopentyl)-2,2’bipyridine. The synthesis of 4-(5-thiopentyl)-2, 2’bipyridine is a multi-step process that requires high purity of each intermediate product. This ligand is unique because it is able to adhere to nanoparticles and increase the favorability of the reaction. Three of these ligands will complex with ruthenium to form Ru(4-(5-thiopentyl)-2,2’-bipyridine)3 (the photosensitizer).
Goldsmith, J.I.; Hudson, W.R.; Lowry, M.S.; Anderson, T.H.;
Bernhard, S.J. Am. Chem. Soc. 2005, 127, 7502-7510.
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The Synthesis of Bis(dichloroacetyl)diamine Derivatives for Cancer Treatment
Natalee Smith
Mentor: Professor B. Malachowski
Interest in bis(dichloroacetyl)diamines (Figure 1) sparked in the late 1950’s to early 1960’s as this class of compounds was found to have antispermatogenic properties. This interest seemed to have dissipated during the late 20th century; however, a renewed interest has been placed in this class of compounds, which, in addition to having antispermatogenic properties, has been found to have cancer treatment capabilities. The aim of my summer research is to synthesize a series of these compounds, by varying the R groups attached. The resulting compounds will then be tested for their effectiveness as therapeutic treatments.
Figure 1
Surrey, A. R, and Mayer, R. J., 1961, The preparation and Biological Activity of some N,N’-Bis(haloacyl)-polymethylenediamines, Journal of Medicinal and Pharmaceutical Chemistry, v 3, no 3, p. 419- 425.
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The Application of the Sequential Birch Reduction Alkylation Cope
Rearrangement to the Synthesis of Natural Products
Iva Yonova
Mentor: Professor Malachowski
One of the greatest challenges in synthetic organic chemistry is creating quaternary carbon centers. Most of the current synthetic tools available to chemists result in a mixture of two stereoisomers, which reduces the effectiveness of the process, as the yield of the desired stereoisomer is automatically halved. Furthermore, the importance of obtaining enantiomericly pure compounds cannot be overstated, as they play a major role in the pharmaceutical industry.
The Malachowski group has been working on utilizing the sequential Birch reduction-allylation and Cope rearrangement (Birch Cope sequence) (Figure 1) as the fundamental tool for the construction of quaternary carbon centers. The group has successfully applied it to the total synthesis of complex natural products such as mesembrine and lycoramine.
Figure 1:
- A carbon atom bonded to four more carbon atoms.
- Molecules with same structure but different spatial orientation
- Only one stereisomer
- Most therapeutic agents contain stereocenters (carbon atoms bonded to four different groups) and one of the enantiomers (or mirror images) is the active drug, while the other may be inactive and innocuous or potentially harmful.
The synthesis of all of the above compounds has been initialized by derivatives of ortho anisic acid (Figure 1) with an attached chiral auxiliary(5), which is obtained by the reduction of the common amino acid L-Proline(6) (Figure 2).
Figure 2
The effectiveness of the Birch Cope sequence depends on the type of molecule to which it is applied – different substituents will have different effects on the labiality of the benzene ring, and thus affect the compounds’ reactivity in the process. My current project involves expanding the scope of the Birch Cope sequence and adapting it to a variety of different substrates. Some of the targets of the project involve aniline and anisole derivatives, alpha phenyl imines, and aminobenzoates (Figure 3). The major challenges that will be faced in the project are the synthesis of the substrate molecules and the adaptation of the Birch reaction conditions to match the specific chemical character of each molecule.
Figure 3
(5) A group that contains a chiral center and is thus able to limit the reactivity of the compound so that only one stereoisomer of the product is formed.
(6) One of the twenty amino acids the human body produces; enantiomericaly pure.
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A Synthetic Pathway Leading to
the Formation of a Potential Inhibitory Molecule
Marisa Winkler
Mentor: Professor B. Malachowski
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan degradation enzyme that is expressed by many tumors to help escape immune detection. Normally, IDO catalyzes an initial step in the degradation of tryptophan to N-formylkynurenine leading to the formation of NAD+. Additionally, IDO is a negative regulator of T-cell activity. T-cells are sensitive to tryptophan catabolism, and depletion of tryptophan or buildup of toxic catabolites can cause T-cells to stop in the G1 phase of cell growth, and therefore cease dividing though mitosis, or can cause cell death. The initial discovery of a relationship between IDO and the immune system occurred in studies of placental trophoblasts which demonstrated IDO activation to prevent maternal immune response to paternal fetal antigens.
Cancer cells, which would normally be destroyed by the immune system, can harness IDO to prevent their destruction and cause proliferation and tumor formation. In fact, elevated levels of IDO-generated catabolites have been found to be associated with a number of cancers. Therefore, inhibition of IDO can promote antitumor immune responses, which allow a specific drug-based approach to treating cancer.
My summer research project involves the synthesis of a molecule which is expected to have inhibitory effects on the indoleamine enzyme. The synthesized molecule mimics an intermediate in the proposed mechanism of the degradation of tryptophan (figure 1), which is why the particular structure has been proposed. The synthetic pathway leading to the formation of the product can also be seen below in figure 2.
Figure 1.
Figure 2. |
Synthesis of (1,1-dimethyl)tridecyl-substituted [n]Phenacenes
Carrie Womack
Mentor: Professor Frank B. Mallory
[n]Phenacenes are compounds consisting of a particular number (n) of benzene rings fused together in a zigzag pattern. They are the one-dimensional analogs of the two-dimensional, highly conductive graphite, and the structural similarity of the two suggests that [n]phenacenes, often referred to as “graphite ribbons”, may have similar electrical properties.
[n]Phenacenes have been previously synthesized in the Mallory Lab with a variety of side-chains to provide solubility. While these side-chains have been sufficient for [n]phenacenes with n as high as 11, they do not appear to be adequate for larger values of n. In order to provide greater solubility, a critical property for these compounds, a new synthesis scheme is currently being attempted with a hydrocarbon side-chain consisting of 15 carbons instead of the 4-7 carbons that have been previously used.
The short-term goal for this project is to synthesize the [3]phenacene and the [7]phenacene derivatives, pictured below. It is proposed that this can be achieved through a multi-step synthesis involving Grignard reactions, Friedel-Crafts alkylations, ring brominations, benzylic brominations, Horner-Emmons reactions and photocyclizations. If the synthesis is successful, it will be extended to larger values of n.
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Strategies of extending the lengths of Phenacenes
Maureen Waweru
Mentor: Professor Frank Mallory
[n]Phenacenes are large polycyclic aromatic compounds with n fused benzene rings in an extended zig zag pattern that resembles long sheets of graphite ribbons. Due to their pi system, these molecules are thought to relate to graphite’s property of electrical conductivity.
Over the years, the Mallory research group has successfully synthesized phenacenes with up to 11 fused benzene rings and are now working towards synthesizing the [15]phenacene and [19]phenacene derivatives. Due to the insoluble nature of these molecules, different solubilizing groups have been attached to the phenacene backbone in order to make the synthesis of larger phenacenes possible. One of the solubilizing groups under investigation is the long-chain polyether CH3 (OCH2CH2)3 O. This group is abbreviated RO in the molecular structure shown below of the [7]phenacene derivative that is a current synthesis target.
Aside from carrying out experiments to determine the effectiveness of these polyether groups as solubilizing side chains, my research will also involve preparing compounds that are required in the initial stages of the multi-step synthesis schemes designed to produce [n]phenacenes with 15 and 19 fused rings.
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Characterization of RNA-Protein Interactions
Julia Lewis and Mithila Rajagopal
Mentor: Professor White
 
L30e is an autoregulatory ribosomal protein. In Saccharomyces cerevisiae, L30e binds to its RNA transcript to inhibit splicing and to its mRNA to repress translation. L30e’s secondary structure consists of six alpha helices and 4 beta sheets. The RNA secondary structure is similar to the 3-D folding of a protein, consisting of motifs such as hairpins, pseudoknots, internal loops, etc. L30e RNA contains a kink-turn motif that is present in both the L30e messenger and ribosomal RNA. The kink-turn causes a sharp bend in the RNA double helix. The kink-turn motif is a canonical stem of Watson-Crick base pairs, three unpaired nucleotides, and a non-canonical stem having two sheared G:A pairs.
The goal of our lab’s research is to understand how some irregular structural features relate to L30e recognition and binding. Previous work in the lab consisted of synthesizing RNA and protein variants to observe the effect of specific mutations on in vitro and in vivo RNA-protein interaction. The RNA mutants were subjected to electrophoresis on a polyacrylamide gel. The rate at which the RNA moves through the gel is related to its shape. The most bent or compact RNA molecule will pass through a gel the fastest because it offers less resistance to the gel. By comparing the relative gel mobilities of RNA mutants, the extent to which each mutation affects the formation of a kink turn can be determined. This makes it possible to determine which mutants assume specific secondary and tertiary structures.
To study the RNA
we first started with bacteria streaks of E. coli which were
grown from already synthesized plasmids BPAU, BP3, KTAU and
KT22. The BP (base paired) plasmid vectors contain DNA in which
nucleotides are perfectly base paired. The KT (kink-turn) contain
DNA which get transcribed into RNA in which nucleotides are
not base paired resulting in the formation of a kink-turn. Mutations
were produced in the KT bacteria to study its effects on the
kink-turn of the RNA. The attempted mutation, KTAU A12U (12th
nucleotide changed from an adenine to a uridine) showed very
poor growth. The remaining bacterial streaks of BP and KT were
used in the isolation of DNA both by small scale (3ml) and large
scale (6ml) techniques. The small-scale resulted in lower yields
but equal purity as indicated by analytical gels and UV-vis
spectroscopy. RNA was synthesized from this DNA by first performing
a restriction digest using restriction enzyme SpeI which cleaved
the circular DNA making it linear and suitable for transcription
into RNA. After transcription, agarose gels were run to
estimate the quantity and purity of RNA obtained. This research
hopes to perform study the effects of various mutations on the
tertiary structure of the kink-turn motif of the RNA using electophoresis
gel experiments (polyacrylamide gels), sedimentation experiments
and atomic Force Microscopy (AFM) which would show how bent
or compact the RNA is (to what extent the kink-turn is affected).
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