Creating a diverse array of structurally distinct, triazine-containing, macrocycles remain the focus of the Simanek group. Until now, this goal has been accomplished through a straightforward 3 step synthetic route with variation of amino acid incorporation and acetal length. Currently two new approaches to macrocycle synthesis are being pursued. The first approach relies on two like monomers coming together: by changing the relative position of groups in the macrocycle, the persistence of shape can be probed. The second approach relies on two different monomers coming together. Using a similar synthetic route, this strategy, if successful, will allow much finer control over design and engineering these molecules for specific purposes. These libraries of structurally diverse macrocycles are important for the long-term goals of establishing rules that can guide pharmaceutical drug design in these under-explored types of molecules.

EUK-134 is a manganese-salen complex widely used in anti-aging skincare formulations due to its potent antioxidant activity resulting from catalytic decomposition of reactive oxygen species. Despite its popularity, the fundamental kinetic properties that govern its efficacy and recyclability are not well understood, limiting its optimization in skincare products. As a result, the study presented here investigates the efficiency, sustained activity, and selectivity of EUK-134 in comparison to the Green lab ligand library by evaluating its turnover number (TON), turnover frequency (TOF), and reaction rate. Results indicate that while EUK-134 demonstrates high catalase-type activity and selectivity, the activity decreases with continuous exposure to H₂O₂, suggesting a need for re-application in real-world scenarios to achieve long-term protection. Additionally, selectivity studies show that peroxidase activity was observed, which may impact the stability of sensitive ingredients in formulations. These findings provide essential kinetic benchmarks to compare future small molecules and optimize EUK-134’s use in antioxidant skincare products. Without a clear understanding of these fundamental properties, we lack benchmarks to compare future small molecules that compete with EUK-134.

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"), [C16-C1pyrr]Br ("IL3"), and CTAB (“IL4”). Variations in the deposition method of the perovskite films 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 IL1 produced through a two-step spin coat deposition method are more photoluminescent than the perovskite films formed with IL2, IL3, IL4 or no IL (control). These results, along with detailed structural characterization of a given perovskite film, will be discussed in this presentation.

Hinges are pervasive in the world today. Most common is a simple mortise door hinge  - defined by the flush stacking of leaves and fully revolute motion. Chemists have long sought to reproduce such structures on the molecular scale. Here, the hinge behavior of large, cyclic molecules is described.  Moreover, hinge motion can be controlled by "gumming up" the parts responsible for motion. While dirt and debris work in the macroscopic world, additional atoms are used in these molecular mimics. Specifically, by increasing the size of groups in the hinge domain, the rate of hinging decreases. Hinge motion is visualized by variable temperature NMR spectroscopy where in, at low temperatures the hinging both faces of the leaves (inside and outside) can be observed. At high temperatures, the hinging speeds up and the inside and outside exchange too quickly to be observed. Unlike hinges of everyday use that require human assembly, the molecular hinges described here assemble themselves. As a result, hinges with identical leaves as well as hinges with mismatched leaves can be prepared. Surprisingly, the results of this assembly process are biased: a statistical distribution of hinges is not observed.  Further studies to understanding this steric (gumming) sorting are ongoing.

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.

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.