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.