Author: Julia Thompson

By: Natasha Narayanan, Bradley L. Merner

[n]para-terphenylophanes are compounds that contain three benzene rings linked at the para, or most remote, positions (Figure 1). The two outer (terminal) benzene rings are connected by a “tether” consisting of a bridge of atoms, where [n] refers to the number of atoms in the tether. Due to this tether connecting the two terminal benzene rings, the central benzene ring of the para-terphenyl unit is distorted out of planarity. Decreasing the number of atoms in the bridge shortens the tether, which increases the distortion of the central benzene ring and the strain energy of the molecule. Our group has developed a short, efficient synthesis of a series of para-terphenylophanes with varying tether lengths. We have recently turned our efforts towards the regioselective functionalization of these compounds for two reasons. First, in order to use these para-terphenylophanes as templates in the bottom-up synthesis of carbon nanotubes, functional group handles must be installed on the benzene rings to perform reactions necessary for elongation in the vertical direction. Secondly, a bent phenol moiety is present in the structure of a natural product known as haouamine A, which was isolated from a tunicate off the coast of Spain in 2003 and has shown promising anticancer activity. We hope to apply the synthetic methodology developed by our group for making bent functionalized arenes to the total synthesis of haouamine A, and in particular to the construction of the macrocyclic core containing the nonplanar phenol.

Beginning with a cyclohex-2-ene-1,4-diol, which serves as a bent precursor to the aromatized system in our synthesis of para-terphenylophanes, we envisioned that we could obtain the α,β-unsaturated ketone from the oxidation of the cyclohex-2-ene-1,4-diol in a [3.3] sigmatropic rearrangement. The dehydration of this α,β-unsaturated ketone would yield the nonplanar phenol. Various oxidation procedures reported in the literature to achieve tertiary allylic alcohol oxidation in a [3.3] sigmatropic rearrangement were tested, including PCC oxidation, IBX oxidation, and DMP oxidation, with no success. The desired transformation was achieved using a literature procedure that employs a TEMPO tetrafluoroborate salt (Figure 2).¹ Attempts to aromatize the compound by eliminating a molecule of water have so far been unsuccessful. Future work will involve improving the yield of the TEMPO oxidation reaction, finding reaction conditions to aromatize the central benzene ring in order to obtain the nonplanar phenol, and investigating other synthetic routes to bent functionalized aromatic rings.  

Recently, some exciting advancements have been made regarding the regioselective functionalization of the two terminal benzene rings of [n]para-terphenylophanes. We predicted that the two tertiary alcohols present in the cyclohex-2-ene-1,4-diol could be used as directing groups to direct the C-H functionalization of the terminal benzene rings. Based on a literature procedure, a tertiary alcohol-directed C-H functionalization reaction was used to successfully install a phenyl ring on one of the terminal benzene rings of a para-terphenylophane (Figure 3).² This regioselective C-H functionalization chemistry can be used as a way to extend para-terphenylophanes into templates of sidewalls of carbon nanotubes. Future work will involve continued efforts to regioselectively functionalize both the central and terminal benzene rings of para-terphenylophanes, and use these installed functional groups as handles with which to extend the curved aromatic system present in para-terphenylophanes.

By: Christina M. Pickering, Connor S. Dobson, Peter R. Panizzi, Allan E. David, Robert D. Arnold

Liposomal drug carriers are nano-scale, spherical particles with a phospholipid bilayer surrounding an aqueous core and are commonly used for chemotherapeutic delivery. Chemotherapy efficacy is limited by toxicity and tumor drug resistance; however, with increased circulation and improved tumor deposition due to the enhanced permeability and retention effect, liposomes increase treatment efficacy and reduce toxicity. However, the chemistry of many efficacious chemotherapeutics prevents their encapsulation within liposomes and poses a challenge for formulating treatments. To respond to this challenge, current drug research is aimed at the development of improved drug delivery technologies, particularly those carriers capable of multi-drug or component delivery because of their flexibility and high applicability.

I hypothesized that composite systems, gold nanoparticles within liposomes, may be used to improve drug delivery of both currently used therapeutics and ones traditionally incompatible with liposomal delivery. I formulated a novel gold-lipidic nanocomposite to capitalize on the drug delivery capabilities of liposomes and the facile conjugation of gold nanoparticles. I proposed new techniques for the formulation of nanocomposites comprised of 2 mm gold clusters capped with glutathione or mercaptosuccinic acid encapsulated within pegylated, long-circulating “stealth” liposomes.

Figure 1 displays the techniques used to formulate the gold-lipidic nanocomposites. Physical characterization was completed using atomic absorption spectroscopy (gold quantification), dynamic light scattering (size distribution), and cell metabolic assays (cytotoxicity). I also studied separation methods for the removal of unencapsulated gold. These nanocomposites can be produced by a simple, scalable method with narrow size distributions around 100 nm and consistent nanoparticle encapsulation. I tested the resulting encapsulation and proposed alternative separation methods to counteract the problems encountered with the dialysis method used in this study.

As part of this study, I compared intracellular uptake and in vivo biodistribution of the gold-lipidic nanocomposites to the standard liposomes. These data support my hypothesis that gold-lipidic nanocomposites can be prepared and they justify preclinical in vivo studies in murine models of human tumors to improve cancer treatment. While there were no differences in intracellular uptake between the standard liposomes and the nanocomposites, we did observe altered tumor deposition relative to tumor volume in nanocomposites compared to traditional liposomes. The initial results were ultimately very favorable and indicate much potential for future work in this area.

Future aims on the project include the co-encapsulation of gold nanoparticles and model chemotherapeutic in liposomes, investigation of the effect of gold nanoparticles on drug encapsulation and release, covalent linkage of paclitaxel to gold to enhance stability and tumor deposition, and exploration of multispectral opto-acoustic tomography to examine the ability of the targeted particles to identify metastasis and improve anti-tumor activity.

By: Doyon Kim, Andras Bezdek

In 1911, Otto Toeplitz conjectured the following: Every Jordan curve in the plane contains all four vertices of a square. In mathematics, a curve is called Jordan curve if it is planar (can be drawn on a paper), simple (does not cross itself) and closed (walking along the curve starting at any point of the curve one will come back to the starting point). We say that a polygon P is inscribed in a curve C if all vertices of P are on C.  So far Toeplitz’ conjecture is solved for curves that are “smooth enough,” but the problem in its full generality is still open. For instance, all curves people can draw with a pencil on a piece of paper, such as circles and polygons, are smooth, and the conjecture is solved for these cases. A closer look at Jordan curves, however, reveals that they can be as complicated as fractals. This complexity renders the problem difficult in spite of its intuitive nature. The general question addressed in this study can be stated as, “Under what condition does a Jordan curve have a specific inscribed polygon?”

We considered the following new variation of the original problem. We said that a polygon P is strongly inscribed in a curve C, if P is inscribed in C and if its interior is contained by the region enclosed by the Jordan curve. We wanted to find a general statement regarding the existence of a polygon P strongly inscribed in a curve C. Even though much research has focused on the original Toeplitz’ conjecture, nobody has researched the problem with this new condition imposed. This condition leads to complications, mainly because it prevents us from using a standard “continuity argument,” where one continuously changes both the size and the position of a strategically selected square and argues that along this change, a desired square must appear at least once.

The following are the theorems we found:

• Theorem 1: For every , there is a Jordan curve that does not have a strongly inscribed triangle whose smallest angle.
• Theorem 2: Every Jordan curve has a strongly inscribed triangle.
• Theorem 3: Let C be a Jordan curve and let T be a triangle. Then there exists a triangle T´ similar to T such that the interior of T´ is contained by the region enclosed by C and two of the vertices of T´ belong to C.
• Theorem 4: Let C be a Jordan curve and let D be a quadrilateral. Then there is a quadrilateral D´ similar to D such that the interior of D´ is contained by the region enclosed by C and two of the vertices of D´ belong to C.

We were able to develop a new geometric method to prove our theorems. Next we will try to generalize Theorems 3 and 4 for all convex polygons. Since we succeeded in proving any Jordan curve contains at least two vertices of a triangle or a quadrilateral of any shape, we expect to prove the same statement for convex polygons with more than four 4 vertices. We also plan to identify classes of Jordan curves for which you can find strongly inscribed triangles of any prescribed shape.

By: Sungil Kim, Michael E. Baginski

Researchers are continuously seeking to develop and improve stock forecasting models by analyzing the past value of a company and predicting future performance based on past data trends. Prior literature on stock analysis focuses heavily on forecasting a single stock price based on its own past data. This type of analysis is susceptible to stock market volatility and not very effective for intraday trading; in addition, it is difficult to apply a method used for a particular stock market sector to other market sectors. In this study, we present a cross-correlation-based forecasting model using sets of closely related stocks to forecast future stock performance.

Cross-correlating two stocks works as follows: When the price of stock A is related to the price of stock B but there is a time delay of K days, predicting stock B’s price based on stock A’s price will reflect the future performance of stock A, K days earlier. For highly correlated pairs, the two stocks are assumed to exhibit a similar pattern in the short term. For a long-term investment, an algorithm must be run continuously that “buys” stock B whenever stock A shows a marked increase in price if the correlation is strong and delayed by K days. The algorithm will also include a sell price once the order is filled that reflects the expected increase in value of stock B.

The proposed forecasting model discussed generates buy and sell signals along with corresponding trade dates and takes the following inputs: a pair of stocks, range of dates, correlation coefficient () threshold, and maximum number of tries. The model first retrieves data from two stocks in a specified range of dates. Then, it calculates the cross-correlation and finds (1) whether the two stocks are strongly correlated ( > -threshold) and (2) whether the time delay (lag) between the two stocks is not zero. After these two conditions are met, the forecasting model generates a buy or sell signal depending on the performance of one stock that influences the other stock with the lag. In case either of the two conditions fails, the algorithm either adjusts the range of dates or changes the pair of stocks when it reaches the maximum number of tries.

The accuracy of the developed model is measured using U.S. stocks from the energy sector, which is more volatile than the technology sector and other indexes (e.g., S&P 500). We chose the energy sector to measure the resistance to volatility, effectiveness and accuracy, and profit per dollar. In particular, we chose Whiting Petroleum Corporation (WLL) and United States Oil Fund (USO), used data from the previous seven years to compute the cross-correlation, and forecasted for 47 days. Results show that the proposed model accurately forecasts the upward trend 15 out of 17 times (88.2%) and the downward trend 26 out of 30 times (86.7%), for a total of 87.2% (Figure 1). Compared to a previous study¹ that uses a data-mining algorithm with lagged correlation with 67% accuracy, the proposed model is significantly more accurate. Furthermore, the proposed model generates 3.2% profit per dollar over the span of the 47-day forecast interval. This result shows that the developed forecasting model is ideal for high-risk, high-return investments. In addition, the model can be used for intraday trading for a pair of stocks with a lag of less than a day.

This research developed a cross-correlation-based forecasting model and demonstrated that a pair of strongly related stocks shows a similar trend in the near future, unless the lag time is too big (greater than several months). The proposed model provides new insight to researchers, investors, and individuals regarding how cross-correlation can improve the accuracy of forecasting highly volatile stocks.

 

By: Caroline E. Hubbard, Heidi A. Kluess, Leslie E. Neidert, Elise K. Mann

Several metabolic polypeptides are present in the saliva. These include peptide YY (PYY), which is a known substrate of the enzyme dipeptidyl-peptidase IV (DPP-IV). DPP-IV cleaves PYY into PYY_3-36, a form that can bind to the Y₂ receptor in the mouth that is involved in sending signals of satiety to the brain (Acosta et al., 2011; La Sala et al., 2013; Moran, 2009). Although it is suggested that satiety is mediated by a mechanism in the mouth, the physiological mechanism is not well understood. The purpose of this study was to investigate the effects of glucose and whey protein on salivary DPP-IV activity, salivary PYY levels, and feelings of satiety.

Twelve healthy college-age subjects participated in the study. During each visit, subjects either consumed whey protein (Optimum Nutrition, Aurora, IL, USA) or glucose (Sierra Mist, PepsiCo, Purchase, NY, USA). During each visit, satiety was measured via a visual analog questionnaire, and samples of saliva and blood were taken for biochemistry measurements (Chaput, Gilbert, Gregersen, Pedersen, & Sjödin, 2010). All measurements were collected pre-condition and thirty minutes post-condition. A fluorometric assay (Scharpé et al., 1988) was used to measure DPP-IV activity in the saliva and plasma. A PYY enzyme immunoassay (PYY_3-36 human, Phoenix Pharmaceuticals, Inc., Burlingame, CA) was utilized to determine salivary PYY protein levels. The visual analog scale contained a series of five questions regarding perceived hunger and satiety, and subjects indicated their answers on a 100 mm line below each question. Satiety composite measures were calculated using a verified mathematical formula from previous literature (Chaput, Gilbert, Gregersen, Pedersen, & Sjödin, 2010).

We analyzed DPP-IV activity, PYY levels, and composite satiety scores. The mean saliva DPP-IV activity levels for the carbohydrate condition and the whey protein condition showed no significant change from pre to post condition (Fig. 1A). There was no significant change between pre and post condition with the plasma DPP-IV for both the carbohydrate and whey protein condition (all: 35.7±8.6U/L). The pre-whey protein condition PYY levels were significantly higher than the pre-carbohydrate condition PYY levels (*p < 0.05 different from Pre-CHO, Fig. 1B). This result can be attributed to natural variation, as the two conditions were counterbalanced. PYY levels did not significantly change from pre to post for either of the two conditions. In the whey protein condition, the satiety composite scores significantly decreased from pre to post (+: p < 0.05 different from pre whey; a: p < 0.05 different from post-CHO, Figure 1C). This decrease in composite satiety score indicated the subjects felt more sated after drinking the whey protein shake. There was no significant change in satiety measure seen for the carbohydrate condition.

These results suggest that macronutrient consumption has a physiological effect on satiety because a significant change was seen in the composite satiety score with the whey protein condition. Although previous literature suggests that there is a mechanism present in the mouth that mediates this physiological response, we did not find any evidence that PYY and DPP-IV are involved. Further research into satiety should be conducted, as understanding the mechanism that mediates this physiological response would allow for better insight into controlling food intake.

By: Taylor Farmer, Peter Livant, Xiaoxun Li

A central challenge to synthetic organic chemists is forming a bond between two carbon atoms. The ability to form carbon-carbon bonds allows one to join together, with precise control, two smaller molecules to form a larger, more complex product. This is a core activity of the synthetic organic chemist.

In our laboratory, we needed compound 2 (Figure 1). Our original method of synthesizing 2 involved three separate reactions, starting with compound 1 (i.e., path a). Our group discovered that 1 could be converted to 2 in one step rather than three by treatment with an excess of sodium hydride (path b). This new reaction is termed a “cascade” because sequential reactions (here three) occur in one reaction vessel.

The cascade reaction forms a carbon-carbon double bond, highlighted in green in Figure 1. Reactions that form a carbon-carbon double bond by joining together previously separate molecules (rather than converting a single bond to a double bond within a molecule) are a somewhat rare type of reaction and quite important in organic chemistry. Examples of this type of reaction are the olefin-forming metathesis reaction, the Wittig reaction, and the McMurry reaction.

Due to the importance of forming a carbon-carbon double bond during our reaction, we strove to understand it in more detail. One means of testing how a new reaction functions is by testing its scope, i.e. the range of materials that can take part in the reaction successfully. One learns what structural changes help or hinder the reaction. At this point only compound 1 had been used in the cascade reaction. We chose three “bromo-nitro” compounds structurally similar to compound 1, viz. 4, 5, and 6 (Figure 1). Like compound 1, all have a bromo (Br) and a nitro (NO₂) group attached to a single carbon in the molecule. After using each of these as the starting material for our cascade reaction, the product yields were found to range from 16-47%. These yields are comparable to those obtained with 1, namely 55% yield.

To make a bromo-nitro compound, a bromo-nitroso compound must be made first. An example is compound 3 (Figure 1) in which a nitroso group (NO) replaces a nitro group (NO₂). Due to the similarity in structure, we proposed that these could be used as cascade starting materials as well. While results with bromo-nitroso compounds are preliminary, we have at least one case in which the carbon-carbon double bond formed. This means that we discovered a new reaction, which will be studied further.

By: James Edmond, Dylan Reedy, Allen Landers, Michael Fogle

Dissociative electron attachment (DEA) is a type of atomic-level process in which a low-energy (sub-ionization energy) electron attaches to a molecule, forming an anion. This molecular anion species is transitory and leads to bond relaxation. As the bond relaxes, it can eject the additional electron and return to the ground state neutral molecule. Otherwise, the bond (or multiple bonds) will break, and one fragment of the molecule will carry the negative charge.

We can study this process using momentum imaging of the anion fragments. This technique relies on crossed well-collimated beams of target molecules and electrons. After the pulsed electrons interact with the molecular beam and a DEA event occurs, we pulse a perpendicular electric field to extract all of the anion fragments formed during DEA. These molecules are randomly oriented; however, we can determine their momentum by measuring their time-of-flight to the detector and their position on the detector. After acquiring millions of DEA events, the data are post-processed to orient the molecules to the incoming electrons to study angular dependences and the energy released during dissociation.

This research provides a benchmark to test theories used to model atomic interactions and gain insight into bond properties, which could lead to achievable methods for controlling or enhancing bond cleavage for chemical processes. This knowledge can contribute to understanding how low-energy electrons cause bond cleavage in biological effects of radiation. Single and double DNA strand breaks seem to be directly linked to low-energy electron cascades caused by radiation. These electrons are in a range where DEA is the predominant process that can break bonds and lead to radical formation even below ionization energies.

Currently, we are studying the CF₄ molecule as one of the many test cases to be benchmarked against this theory. We aim to measure the DEA dynamics related to this molecule as it seems to exhibit some mechanics that are not predictive based on other molecular systems. This abnormality has been hinted at by the observations of another research group, but the results we have obtained so far seem to contradict their results. This illustrates the primary importance of studying a wide range of molecular species for benchmarking and ensuring reproducibility.

Figure 1. Yields of cyclohexene oxide generated in aqueous solutions at various constant pH values (A) Reaction conditions: [Ga(phen)2Cl2]Cl = 0.75 mM, [alkene] = 75.0 mM, [peracetic acid] = 151 mM. (B) [Ga(bispicen)Cl2]Cl = 0.85 mM, [alkene] = 85 mM, [peracetic acid] = 169 mM. Both series of experiments were performed under air at 25 °C.

By: Sean M. Bittner, Lee Robeson, Edward W. Davis

Effective wound treatment is a prominent issue in medicine. Identifying and treating persistent infections is particularly important, as untreated infections can rapidly escalate. Halloysite, a naturally abundant, nontoxic clay nanotube, can be loaded with 10-30 wt % antibiotic, extending release from minutes to hours or days, and has been shown to improve the drug encapsulation of polymer films when admixed. However, the literature surrounding halloysite is deficient in some areas. Although poly (vinyl alcohol) (PVOH) and poly (methyl methacrylate) (PMMA) composites are common, experiments with other biologically relevant polymers are limited. Additionally, the literature primarily consists of experiments using tetracycline, a small, water-soluble antibiotic. My project attempts to address these deficits by (a) investigating drug release  from poly (lactic-co-glycolic acid) (PLGA) composite films, a polymer widely used in the medical community, and (b) investigating the release of novel antibiotic  gentamicin sulfate and comparing to that of tetracycline.

To evaluate tetracycline release from composite films, drug-loaded halloysite/PLGA film slices were added to deionized water and held at 37°C in a shaking water bath. Samples were periodically tested using a UV spectrophotometer. Controls were prepared with pure PLGA, unloaded halloysite/PLGA composites, and tetracycline-loaded PLGA.

On release, the “burst” of drug content is significantly reduced and release is prolonged. On comparison of the 5% drug-loaded halloysite (DLH)/PLGA composite and equivalent polymer, an approximate 30% decrease in release rate is observed, indicating considerably better encapsulation. A similar relationship is observed between the 10% DLH/PLGA film and equivalent, yielding ~75% reduction. Drug encapsulation was also demonstrated by comparing the 5% drug-loaded polymer with the 10% DLH/PLGA film. Despite the composite having twice as much loaded drug, the drug released after five hours was much higher in the 5% pure polymer, again indicating that halloysite incorporation is effective at mitigating antibiotic release.

The tetracycline results matched expectations from previous work and the literature at large. A block ratio comparison study also shed light on how this ratio impacts drug release; it was noted that increasing lactic acid yielded a higher initial burst and overall release rate, indicating some insolubility of tetracycline in lactic acid. However, it was noted that halloysite incorporation into an 85:15 (LA:GL) composite film tailored release between a pure 50:50 film and a 50:50 composite film, which is beneficial in the case that a lactic acid-based polymer is needed for drug delivery.

The results of novel antibiotic trials were inconclusive, owing to unforeseen complications caused by heating composite films. Release profiles suggested significant drug degradation, as the total mass in solution over time appeared to decrease. Ultraviolet (UV) analysis of gentamicin solutions, however, showed that the drug produced consistent absorbance spectra. Components of the o-phthaldialdehyde solution, which is used as a drug marker in UV testing, were similarly tested and were determined to be chemically stable. As a result of these tests, combined with the negligible impact of heat treatment on halloysite below 100°CI, it is suspected that the PLGA itself masks the absorbance signature of gentamicin.

Moving forward, several areas should be investigated. The immediate focus should be alternative quantification for gentamicin. Several alternatives are being explored, with High Performance Liquid Chromatography being the most popular. It is also important to measure degradation rates of the composites as a result of halloysite incorporation, as the degradation profile of the chosen material needs to fit the application.