Platinum nanocrystals on Silicon nanotubes (PtNCs-pSiNT) exhibit significant anticancer activity via an apoptotic mechanism. To enhance the specificity of this material, we attach folic acid (FA) to the nanotube surface to target folate receptors (FARs) overexpressed in cancer cells. This conjugation is successfully demonstrated through X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FT IR). Cell viability assays show an enhanced cytotoxicity toward HeLa cells relative to its non-FA containing analog.

Platinum-based therapeutics, exemplified by the FDA-approved anti-cancer drug cisplatin, are a mainstay in treatment of a range of different cancer types.3 Although this drug can form an adduct with DNA and induce apoptosis, many studies have confirmed that cancer cells can develop resistance to this treatment. Alternatively, small Pt nanocrystals (Pt NCs) have demonstrated arrested growth and apoptosis in cancer cells as a consequence of DNA platination and enhanced strand-breaks initiated by leaching Pt(II) ions from the NC surface in the acidic intracellular environment. Small Pt nanocrystals whose size is less than 3 nm demonstrate a higher reduction in cell viability than those with larger size, presumably owing to a relatively greater exposed surface area for dissolution. This observation, coupled with the identification of downregulation of multiple genes critical for cancer cell proliferation after treatment with Pt NCs, has led to an observed reduction in addressing drug resistance. Such nanocrystals tend to aggregate extensively in an aqueous environment, however, and we have developed well-defined Silicon nanotubes (pSiNTs) as a scaffold for effective nanocarrier for drug delivery of such PtNCs, taking advantage of nanotube high surface area, biocompatibility, and biodegradability. Functionalization with 3-(aminopropyl)triethoxysilane (APTES), followed by incubation with dilute K2PtCl4 solution results in the formation of PtNCs-pSiNTs well dispersed on the pSiNTs to avoid aggregation and release the platinum as the pSiNTs are resorbed over time, which results in significant cancer cell cytotoxicity-ty. To enhance the specificity of this material we conjugate Folic Acid (FA) to the Pt surface using as a Glutathione (GSH) linker, with the goal of enhanced targeting of overexpressed FARs and more selective cancer cell uptake.

Chameleonicity, or the ability for a molecule to change its shape to match its environment, is an often-beneficial quality of potential drug candidates, allowing for greater cell permeation. Our group has previously reported several macrocycles exhibiting dynamic hinging motion, allowing the macrocycles to adopt various conformations and giving rise to chameleonic qualities. However, the extent of hinging (e.g., the rate and barrier to hinging) were contingent on the bulk of an amino acid’s side chain. Here, five 24-membered triazine-based macrocycles are introduced with varying alkyl substituents on the hydrazone moiety of our macrocycles, distant from the hinging axis. The macrocycles are obtained by a facile three step process in high yields at each step, with the macrocyclization yielding quantitative folded and dynamic macrocycles. Using rOesy NMR, the macrocycles’ conformation and rotamer state is shown to be preserved. Variable-temperature NMR reveals that the hinging motion is mostly unaffected by the distant hydrazone substitution, further establishing the location and pathway of the hinging axis. The minimal impact of hinging via these substituents allows for varying groups to be placed away from the axis, preserving the dynamic motion but allowing for tuning of pharmaceutically relevant parameters (e.g., lipophilicity/water solubility with varying alkyl chains) or installment of bioactive moieties. Permeability studies with PAMPA show acceptable passive permeation of the alkyl hydrazone macrocycles, with permeability dependent on lipophilicity and dynamic motion. These results further indicate the ability of these macrocycles to be valid scaffolds for intracellular drug development.

Typically, the costs associated with the synthesis, isolation, and purification of high value molecules/materials as well as environmental/health concerns related to the overall process are disregarded due to perceived profits that could be obtained from the use of the final products. However, as the scale of production of these materials increases, the need for more environmentally benign, sustainable, inexpensive, yet still facile and efficient processes increases exponentially.

Squaraine dyes are versatile, high-value fluorescent molecules, with a very broad and diverse range of applications due to their absorption and emission in the infrared spectral region. However, vast majority of literature syntheses of these dyes utilize toxic, volatile solvents. In this presentation, we will outline our current efforts on the use of green solvents, solvent-free and mechanochemical routes to various types of squaraine dyes. Furthermore, we will present sustainability and cost-effectiveness estimates as guiding tools for the future development of all around-efficient synthetic protocols for various types of squaraine dyes.

The inclusion of a pyridine moiety in the skeleton of tetra-aza macrocycles introduces rigidity while also introducing a handle by which the electronics and basicity of the ligand can be tuned. Metallation of these pyridinophanes has resulted in active mimics for metalloenzymes, such as superoxide dismutase mimics. However, recent work has explored their potential for industrially relevant catalytic reactions. Previous studies of iron RPyN3 complexes showed moderate success for a direct Suzuki-Miyaura C-C coupling reaction. In that work, it became clear that the substitution on the 4-position of the pyridine ring offered significant influence over the efficacy of the catalyst: the electron donating groups offer a better handle of modification of the electronic properties of the iron center, but the electron withdrawing groups increased the catalytic activity of the complex. In this presentation we introduce a second pyridine ring to the macrocycle skeleton, which includes a second position for modification, and compare the activity of this new RPy2N2 iron complex series to the previous RPyN3 series. Yields within this new series of iron complexes will be compared along with characterization of the respective complexes to understand what properties mitigate reactivity.

Oxidative stress is caused by the accumulation of reactive oxygen species (ROS) in the body and is a key player in many maladies, including neurological diseases like Parkinson’s and Alzheimer’s disease. Superoxide dismutase (SOD) enzymes are capable of transforming the common ROS molecule superoxide (O2-) into less toxic species such as H2O2 or O2, thus protecting the body from harmful reactions of superoxide. Synthetic metal complexes show promise as SOD mimics and can be effective alternatives to therapeutic dosing of SOD enzyme for oxidative stress. In this work, we present a series of 12-membered tetra-aza pyridinophanes (Py2N2) and the corresponding copper complexes with substitutions on the 4-position of the pyridine ring. The SOD mimic capabilities of the Cu[Py2N2] series were explored using a UV-Visible spectrophotometric assay. Spectroscopic, potentiometric, and crystallographic methods were used to explore how the electronic nature of the 4-position substitution affects the electronics of the overall complex, and the complex’s activity as a SOD mimic. This work is an initial step toward developing these Cu[Py2N2] complexes as potential therapeutics for neurological diseases by mimicking SOD’s capabilities and protecting the body from oxidative stress.

The therapeutic potential of macrocycles provides a tantalizing opportunity in drug discovery. The design criteria, such as solubility properties, for macrocycles is only beginning to be understood. One of the significant limitations to such investigations is the synthetic challenge that macrocycles provide and the need for comparison across similar molecules. This study describes the creation of a library of macrocycles to probe and ultimately to engineer partition coefficients. Recently, the quantitative dimerization of monomers to yield 24-atom macrocycles has been described. Historically, a trichlorotriazine is substituted with BOC-hydrazine, an amino acid, and an auxiliary amine (which has been limited until this point to morpholine or dimethylamine). Subsequently, an acetal is installed and treatment with acid results in quantitative dimerization to form macrocycles. To increase the efficiency of synthesis in this study, the acetal is installed prior to the auxiliary amine—the point of divergence. Here, five auxiliary amines were installed to give five monomers. These five monomers were combined in equimolar amounts and treated with acid to induce dimerization to yield five homodimers and ten heterodimers. The octanol:water partition coefficients of these molecules reveal a compensatory effect of substitution. That is, at pH 7, the partition coefficients of the heterodimers lie between the values of the corresponding homodimers. At this pH, the logP ranges between 1.9 and 4.3, indicating that relatively small molecular changes result in large variation in the logP of these macrocycles. The ability to engineer one property—the partition coefficient—suggests that a secondary property—shape—is conserved, a hypothesis borne out by NMR spectroscopy.

Asphaltenes constitute the heaviest, most diverse, and most chemically unresolved component of petroleum crude oils. Asphaltene mixtures are structurally complex, containing thousands of distinct species with a broad range of molecular weights, functional groups, and aromaticity. The structural diversity of asphaltenes, along with their tendency to aggregate, has hindered a complete understanding of the asphaltene component of crude oil. Modern asphaltene studies have deciphered hundreds of individual asphaltene structures through atomic force microscopy (AFM). The structural diversity and expanding chemical knowledge of asphaltene structures necessitates a way to store and easily retrieve and analyze this information. Additionally, much remains unknown about the connection of these imaged structures to ensemble properties of asphaltenes in crude oil. Herein, we address these two points via creation of a database of 69 published asphaltene structures. Quantum chemistry calculations are run to determine molecular properties of these individual asphaltenes and are stored on the database. These properties include molecular weight, solubility, aromaticity, dipole moment, and HOMO-LUMO gap. The database is exploited to generate graphs—such as the UV-Vis absorbance spectrum—using these computed properties to allow for a more complete chemical description of the ensemble properties of asphaltene mixtures. Our computational predictions give a more complete chemical description of previously determined individual asphaltene structures and help contextualize them with respect to their ensemble properties in crude oil.

Although chromatography is a reliable purification method in protein downstream processing, it has several limitations such as loading capacity, scalability and operation costs. These are important drawbacks especially for proteins generated from cell cultures with a high yield. Protein crystallization, which does not suffer these limitations, is regarded as a promising alternative to chromatography for protein purification. However, since protein crystallization is a complex not-well-understood process, protein crystals are often produced at low yield and with poor reproducibility. Thus, its implementation in protein purification protocols remain challenging. In our lab, we designed a new strategy for enhancing protein crystallization from metastable protein-rich droplets generated by liquid-liquid phase separation (LLPS). This strategy is based on the use of two additives; the first additive is needed to induce LLPS in protein aqueous solutions, while the second additive modulates the ability of protein-rich droplets to produce crystals. A protocol for determining yields of LLPS-mediated protein crystallization was also developed. This poster reports our experimental results on yield of lysozyme crystallization in the presence of NaCl (0.15 M) as an LLPS inducer and 4-(2-hydroxyethyl)-1-piperazineethanesulfonate (HEPES) as a modulator. Our results show that addition of HEPES (0.10 M) significantly boosts lysozyme crystallization yield from ≈5% (no HEPES) to 92%. The effect of temperature and incubation time on the yield of protein crystallization yield was also investigated. Our results reveals the key role of LLPS in enhancing protein crystallization.

Small molecules are reliable and pervasive pharmaceuticals because critical drug characteristics are predictable including solubility and membrane permeability. In addition, small molecules are typically inexpensive to produce and their mechanisms of action subscribe to a common paradigm vis-à-vis blocking an enzyme active site. In contrast, nature employs elaborate machinery to make large molecules, oftentimes rings (or macrocycles). Drug companies avoid these because the rules for predicting behavior are under-explored and the paradigm used for action is different vis-à-vis blocking protein-protein interactions. Moreover, they are costly and laborious to make. To contribute to an understanding of drug design for large molecules, our group is preparing a series of large molecules (macrocycles). The lead adopts a beta-sheet conformation in the solid state, but its behavior in solution is unknown. Here, a second member of the class is described wherein alanine replaces glycine in the macrocycle to provide additional handles to study conformation and the effects that structure has on critical parameters. The 26-atom macrocycle is synthesized in a three-step process. The reaction of a triazine core, and the addition of BOC-hydrazine, alanine, and dimethylamine yields the first intermediate which undergoes elaboration with a 4-carbon acetal group using traditional peptide-coupling strategies (HBTU). Dimerization of the resulting monomer occurs in a 1:1 mixture of dichloromethane and trifluoroacetic acid. Reaction progress is followed by thin-layer chromatography and the identity of the products is confirmed by 1H and 13C NMR spectroscopy. Conformational analysis rests on 2-D 1H NMR spectroscopy. The molecule will also be subjected to analysis for solubility and membrane permeability. In the longer term, these beta-sheet mimics will be used to disrupt protein-protein interactions with an emphasis on the BRCA1-PALB2 interaction implicated in breast cancer.

Utilizing the supportive structure of hydrogels, the semiconducting character of porous silicon (pSi) membranes, and the biodegradability of both, a unique biosensor for the chemical analysis of health-relevant analytes can ideally be created.
Alginate-based hydrogels are water-infused, biodegradable polymer networks. These are particularly useful because of their environmental abundance, and their ability to interface well with human skin. These characteristics also make them an ideal medium for supporting pSi membranes and simultaneously assimilating them into a wide range of tissues.
Porous silicon (pSi), a highly porous form of the elemental semiconductor, is utilized to measure and conduct electrical signals throughout the hydrogel matrix. In diode form, these membranes exhibit measurable current values as a function of voltage, which can be used to detect bioelectrical stimuli such as the concentration of physiologically relevant ionic species (e.g. Na+, K+, and Ca2+).
Recent experiments center on integrating pSi membranes into various aqueous environments and hydrogels to test how variations in ion concentration affect the flow of electrical current as a function of applied voltage. pSi membranes are fashioned into diodes upon the attachment of 0.25 mm diameter copper wire using silver epoxy and annealing. An electrochemical cell is created by placing two pSi membranes parallel each other in an electrolyte composition. Current is measured as a function of applied voltage (typically from 0-5 V) for systems with differing NaCl concentration.
As expected, the magnitude of maximum current response is proportional to ion concentration present in the electrolyte, with an order of magnitude amplification or more of measured current for a given voltage upon immersion of the electrodes in an alginate hydrogel matrix relative to water alone.
This presentation will focus on initial diode fabrication protocols, as well as establishing limits of detection for simple ions species present in human sweat. More refined strategies are also envisioned, including the development of methods for stabilization of sensor performance along with miniaturization of the sensing platform itself.

Testing a Computational Workflow for Drug Design: pKa and logP from the SAMPL7 Blind Challenge
Katie Zabel
Advisor: Benjamin Janesko
Being able to produce accurate predictions of pKa for various molecules is an ongoing effort in computational chemistry. Drug companies and industries are constantly seeking accurate predictions of pKa and lipophilicity for molecules that are possible drug candidates. Accurate predictions of these values means that time, money, and effort won’t be wasted synthesizing molecules that aren’t going to be effective drugs. The Janesko group has developed a workflow that uses CREST for conformational analysis and (M11plus/def2TZVP/SMD) DFT calculations to identify a molecule’s pKa. The DFT calculations process and refine the relative energies of the stable conformations. The goal of this project is to benchmark the current workflow against the SAMPL7 challenge, which will test the workflow’s outperformance of the best quantum-mechanical methods from 2021. The SAMPL challenge is a competition that asks participants to predict the properties of molecules that have never been synthesized. These molecules will then be created in labs and their properties will be accurately tested. Comparison of the competitor's predicted properties to the true values measured will assess the accuracy of the competitor's predictions. If the prediction of pKa using the current workflow is accurate based off the benchmark against the SAMPL7 challenge, then the workflow could be entered into the next SAMPL Blind challenge.

N-terminal acetylation is essential for the stability, activity, and targeting of proteins in eukaryotes. However, most eukaryotic proteins are not acetylated when expressed in bacteria. Therefore, it is of practical significance to control N-terminal acetylation of recombinant proteins in bacteria. RimJ is an N-terminal acetyltransferase (NAT) known to acetylate many recombinant proteins with a narrow substrate specificity in E. coli. This project is aimed to increase the applicability of RimJ for the N-terminal acetylation of a broad range of recombinant proteins.
Based on the AlphaFold-predicted structure of E. coli RimJ, we predicted that six amino acids (Y35, E46, R49, Y106, Y170, and L171) may recognize substrate proteins in the active site. We created RimJ variants, in which one or two of these amino acids are changed to alanine, a small neutral amino acid, so that the active site becomes larger to accommodate substrate proteins containing bigger N-terminal amino acid residues. The RimJ variants were created using site directed mutagenesis, confirmed by DNA sequencing, and co-expressed with Z domain mutants that were not acetylated by the wildtype RimJ. The Z domain mutants were isolated by immobilized metal ion affinity chromatography and analyzed by mass spectrometry for their N-terminal acetylation patterns.

In the past two centuries, tuberculosis (TB) has killed over 2 billion people. TB is an airborne contagious infection that usually attacks the lungs and can spread to the brain and spine. Today TB is treated with 6-12 months of antibiotics and if the medication is ended early the treatment is ineffective. There are also drug resistant forms of TB that are caused by mutations of the bacteria and this process is sped up by the overprescribing of antibiotics which is a growing problem. Dr. Jeffrey Aube created a drug that attacked both non replicating and replicating TB bacteria in the body. This was a major step from previous medicines that could only attack one. We are creating a library of TB drugs that are customizable, efficiently made, and easily purified. These customizable drugs will not only create a large range of effective medicines but also can treat TB that is resistant to antibiotics. Tuberculosis is still one the leading infectious disease killer today, claiming 1.5 million lives annually and we are making drugs that could change that and save millions of lives.

Pyridinophane molecules have recently been shown to have both antioxidant and pharmacological properties suitable for therapeutic applications targeting neurodegenerative diseases, including Alzheimer’s. We have synthesized derivatives of the parent molecules with substitutions on the pyridine ring (L1) or on the ‘side’ of the macrocycle (L2) designed to increase the antioxidant activity beyond that of the parent molecule in hopes of producing a molecule suitable for pharmacological testing in animal models. The lab is currently working towards substituting on the ‘bottom’ of the macrocycle (L3) to characterize and compare substitutions at each of the three positions.

Macrocycles are molecules containing at least one ring composed of 12 or more atoms. Macrocyclic drugs have been used clinically for decades. Many interfere with protein-protein interactions. Therapeutic intervention requires that macrocycles remain flexible to facilitate the adoption of different conformations. Specifically, small compact hydrophobic conformations are required to cross cell membranes. The ability of a macrocycle to perform these contortions is predicted by its octonal:water partition coefficient, its so-called logP. Macrocycles (as well as small molecule drugs) that are suitable for oral delivery have a logP value <5. In this study, methionine containing macrocycles are studied. The studies commence with the synthesis of a macrocycle with a dimethylamine auxiliary group that allows for solution-phase NMR analysis. Upon formation of the macrocycle, oxidation to sulfone and sulfoxide derivatives was executed. These macrocycles are of interest because the impact that oxidation has on log P values has not been reported. Additionally, S-oxidation could change the conformation of the molecules. Synthesis beings with substitution of trichlorotriazine with BOC-hydrazine, followed by treatment with methionine in basic conditions. The final substitution of the triazine installs the auxiliary group, dimethylamine (NMR). Amidation with 1,1-diethoxypropyl amine using a peptide coupling reagent yields the monomer. Cyclization using TFA yields the macrocycle. NMR spectroscopy confirms macrocyclization and gives insight into the solution conformation of the molecule. Oxidation strategies and the results of logP analysis will be developed.

Proper functioning of BRCA1 and PALB2 are essential in preventing tumor formation. Upon detection of DNA damage, BRCA1 binds to PALB2, leading to formation of the BRCA1-PALB2-BRCA2 DNA repair complex which is recruited to double-stranded break sites. Mutations in the genes coding for BRCA1 and PALB2 may disrupt this binding interaction, causing obstructions in DNA damage repair and increased breast cancer risk. Variants of unknown significance (VUS) found in breast cancer patients are genetic variants whose impact on the health of individuals are not yet known. Our study characterizes the effects of these VUS on the BRCA1-PALB2 binding interaction. Site-directed mutagenesis was used to generate BRCA1 and PALB2 VUS. It was found that the binding event between BRCA1 and PALB2 is enthalpic in nature and can be measured adequately via isothermal titration calorimetry (ITC). Thus, ITC was employed to identify whether the VUS disrupted binding. ITC data suggest that several PALB2 and BRCA1 VUS exhibit disruptions of the BRCA1-PALB2 binding interaction, but to varying degrees. We will share the data for variants tested thus far and emerging themes for prediction of the roles residues in both proteins play in the vital interaction.

Barriers to rotation within triazine compounds have been previously explored by Katritzky and Birkett [1-2], but these studies have been limited to differences in the substituent groups on the triazine as well as the degree of substitution (mono, di, tri). This study explores how the barriers to rotation within triazine containing compounds are affected by solvent and protonation state. Overall, these molecules are of interest due to their wide range of applications in dendrimer and macrocycle synthesis as well as pharmaceutical drug development [3-4]. The results of this study illustrate how solvent selection can significantly impact the distribution of rotational isomers (rotamers) and how barriers to rotation can be increased by protonation of the triazine ring.

Alzheimer’s Disease (AD) affects over 6.5 million Americans over the age of 65. Previous research links AD with the aggregation of Amyloid-beta-40 (AB40) in the brain, which creates neurotoxic plaques, causing further development of AD in the brain. A potential therapeutic mechanism in the treatment of AD is using drugs that will prevent the formation of these plaques, which is possible with Metal Chelation Therapy.
Metal ion chelation ideally stops metal ions from aiding in the aggregation of AB40. However, to deliver metal chelating agents to the brain, a drug-delivery mechanism is required that will be able to deliver this medicine across the Blood-Brain Barrier. Porous silica is a potential drug delivery material due to its particle size, high loading capacity, tunability, and biocompatibility. Along with these characteristics, porous silica can create a “sustained” release of a given drug, allowing for a slow and steady release profile, reducing the risks of medication side effects.
This project seeks to establish the optimal loading capacities of a class of potential AD therapeutic molecules known as pyclens into porous silica, each with different pyridyl moieties and chemical functionalities along the rim of the molecule. Encapsulation efficiencies measurements for these pyclen derivatives reveal loading percentages in the 10-19% range, varying by pyclen identity. Additionally, release studies monitored diffusion over time to find which pyclen molecule achieved “sustained” release. All loaded pyclen species were able to show sustained release after 20 minutes. Additional release studies of these molecules in the presence of copper (Cu2+) remain to be completed to ascertain the ability of release drugs in the presence of Cu2+ to inhibit AB40 aggregation, followed by independent assays of AB40 solubility under such conditions.

Two proteins, BRCA1 and PALB2 are known to aid in DNA damage repair through homologous recombination. Both proteins are phosphorylated upon DNA damage, and we hypothesize that the phosphorylation of these proteins acts as an “on switch” to allow the proteins to interact and form the DNA repair complex. To test this hypothesis, we mimicked phosphorylation on the BRCA1 protein to test the binding affinity between BRCA1 and PALB2. Phosphomimicking mutants are created by mutating an amino acid with the ability to be phosphorylated and acquire a negative charge, such as threonine (T) or serine (S), to a negatively charged amino acid, such as glutamic acid or aspartic acid. Recent research has shown that specific phosphorylation sites, such as T1394 in BRCA1 are essential to DNA damage and repair in cells. We have created a phosphomimic mutant in this specific T1394 site by mutating threonine to glutamic acid. We are currently measuring the effect that this mutation has on the ability of BRCA1 to bind to PALB2 in vitro. The obtained data will reveal whether phosphorylation has an impact on the interaction between these two proteins or not.

Metal-halide perovskites are crystalline materials that work as a semiconductor in both Light Emitting Diodes (LEDs) and solar cells. In general, perovskites possess the formula ABX3. For this project, the A site is an organic molecule such as Methylammonium (MA), the B site is Lead, and the X site is Bromide. While perovskites are easily fabricated, their crystal size and number of defects present are challenging to control. Defects cause LEDs to be less stable and/or less photoluminescent (bright) and cause solar cells to be less efficient at converting light to energy. One approach to reduce the number of defects is to use ionic liquids during perovskite formation. Ionic liquids are compounds made of ions in the liquid state due to a low melting temperature. They can be added to the perovskite precursor solution to slow down the crystallization process so that fewer defects are created. The goal of this project is to create new metal halide perovskites in the presence of selected ionic liquids, evaluate their structure and photophysical properties, with the long-term goal of creating new LEDs that are both stable and efficient.

In this project, cetyl-ionic liquids (cetyl meaning 16 carbon chains) were investigated for their effects on perovskite structure and light emission. The three ionic liquids were investigated: [C16-mim]Br (referred to as "IL1"), [C16-py]Br ("IL2"), and [C16-C1pyrr]Br ("IL3"). Variations on the addition method of ionic liquids to the perovskite precursor were studied as well. It was hypothesized that the inclusion of cetyl-ionic liquids will protect the perovskite films from the environment (increasing stability) by providing a hydrophobic layer on the surface and will improve the electronic properties by filling in pinholes that cause defects. It is found that perovskite films with IL3 are more photoluminescent than the perovskite films formed with IL1, IL2, or no IL (control). Preliminary experiments varying the addition method of IL3 during film formation have shown that the perovskite films are brightest when IL3 is added to both the precursor and the antisolvent layers at the beginning of the fabrication process. These results, along with detailed structural characterization of a given perovskite film, will be discussed in this presentation.

To fight disease, pharmaceutical companies have historically prepared small molecules designed to interfere with specific sites on proteins (enzymes) to prevent chemical reactions from taking place. However, a second paradigm for interfering with proteins has gone largely unexplored--blocking protein-protein interactions. To accomplish the latter, large molecules are needed to bind to large areas on the protein target. However, large molecules present additional challenges. Typically, they are hard to synthesize, not orally available, and typically cannot cross cell membranes. Nature has designed large molecules like cyclosporin that should not work as drugs based on our current understanding. Despite its size, cyclosporin is orally available and can cross cell membranes. This research explores the design, synthesis, and conformational analysis of similar large ring-shaped molecules, so-called macrocycles. In this work, we are increasing the size of the ring-shaped molecule. By increasing the size of the ring-shaped molecule and varying the amino acid (in this case, valine), we are expanding the possible ways in which our macrocycle may interfere with protein-protein interactions. Here, a 26-atom macrocycle is reported. 1H NMR spectroscopy reveals a protonated molecule that is highly dynamic which has access to a beta-sheet conformation.

Macrocyclic drugs adopt multiple conformations--a behavior referred to as chameleonicity--to navigate hydrophobic cellular membranes and aqueous intracellular environments. The rules for understanding this behavior are beginning to emerge through studying existing drugs and the synthesis of model systems. Historically, one challenge to macrocycle synthesis is low yield reactions. To this end, dynamic covalent chemistry has been explored. Here, macrocycles are afforded readily by dimerization with the formation of two hydrazones.

The efficiency of the macrocyclization reaction led to the hypothesis that upon formation of the first hydrazone, the acyclic intermediate was preorganized to place the hydrazine and acetal in close proximity thereby reducing the likelihood of oligomeric or polymeric products. The preorganization could result from a network of hydrogen bonds. Moreover, in an acidic environment, wherein the triazine ring is protonated, the opportunity for bifurcated hydrogen bonds emerge. Computation has been used to identify sites for protonation and the energetic contributions of hydrogen bonding.

To explore templating and the role of protonation in the formation of hydrogen bonds, model systems were prepared that emulate ‘half’ of the macrocycle. The acetylated aminoacetal offers a well-resolved NMR spectrum. In contrast, hindered rotation about the triazine-N bond leads to a mixture of rotamers in the hydrazine component. However, upon condensation, a single rotamer is observed and resonances corresponding to the hydrogen bonded protons emerge downfield between 7-12 ppm. Computation provides estimates of the energetic contribution of the bifurcated hydrogen bond as well as the hydrogen bond formed in the absence of protonation. The results of titration and variable temperature NMR experiments will also be described.

The mis-regulation of reactive oxygen species and transition metal ions contributes to the onset of Alzheimer’s Disease. Reactive oxygen species are a natural byproduct of metal redox cycling that occurs within the body and are important in processes like homeostasis and various pathways of cell signaling. Two series of pyridinophane ligands were produced and evaluated for the ability to target the molecular features of Alzheimer’s Disease. The functionalized pyridinophanes were chosen to analyze their blood-brain barrier permeability and radical scavenging ability when included within a molecular scaffold. Preliminary results with the DPPH assay indicated a significant increase in radical scavenging activity for ligands containing electron-donating substitutions in comparison to the parent ligands. These results warrant further exploration into the mechanism of the activity observed.

Petroleum crude oil, unconventional crudes, and renewable bio-crudes are essential materials in our everyday lives. They fuel vehicles, heat buildings, provide electricity, and are used to produce a multitude of other materials, such as plastics and solvents. Crudes are highly complex chemical mixtures, estimated to contain between 100,000 and 100,000,000,000,000,000 unique molecules. Since 2015, single-molecule imaging has visualized hundreds of chemical structures, and historical literature has published thousands of proposed structures. This project builds an open database populated with published crude structures enabling data-driven analysis of these structures, and detailed workflows, allowing for easy future insertion of new molecules into the database. This database can be used to make calculations and predict characteristics of molecules, such as viscosity, density, and reactivity, which are all critical in refinery plants, transportation, and usage of these fuels. Performing queries on the molecules in the database to filter for specific characteristics allows scientists to develop more successful experiments by refining their hypotheses to account for the query results displaying possibilities of their desired outcome.  

This research aims to understand how to design and control molecular hinges. The molecular hinges of interest are nano-sized equivalents of door hinges. Such hinges could find applications in new materials or the design of new drugs.

The foundation for this research was the observation that a large, ring-shaped molecule - a so-called macrocycle – prepared by a colleague folded and unfolded rapidly at room temperature. Two research questions arose from this observation: was the hinge behavior unique to this molecule, and could the hinging rate be controlled?

Addressing these questions required the three-step synthesis of a related macrocycle. This new molecule had groups equivalent to putting grit around the hinge's pin. The difference in the rate of hinging motion due to the addition of these groups was observed using a technique called variable temperature NMR spectroscopy.

The results of this work revealed that hinging is a general phenomenon for some of these macrocycles. Second, the 'molecular dirt' designed into this new hinge reduced the rate of hinge motion from 2000 times per second to 20 times per second.

This work is being written up for communication to the Journal of the American Chemical Society based on the novelty of this molecular device and the scientific community's interest in molecular machines.