RESUMO
Chemoselective reactions allow near-precision control over the polymer composition and topology to create sequence-controlled polymers with similar secondary and tertiary structures to those found in proteins. Dendrimers are recognized as well-defined macromolecules with the potential to mimic protein surface functionality due to the large number of functional groups available at its periphery with the internal structure acting as the support scaffold. Transitioning from using small-molecule dendrimers to dendritic macromolecules will not only allow retention of the high peripheral functionality but also provide an internal scaffold with a desired polymer composition within each generational layer. Here, we exemplify a systematic approach to creating a dendritic macromolecule with the placement of different polymer building blocks in precise locations within the internal structure and the placement of three different amino acid moieties clustered at the periphery. The synthesis of this ABC dendritic macromolecule was accomplished through iterative chemoselective reactions.
Assuntos
Dendrímeros , Dendrímeros/química , Aminoácidos/química , Polímeros/química , ProteínasRESUMO
Cancer stem cells (CSCs) make up a small population of cancer cells, primarily responsible for tumor initiation, metastasis, and drug resistance. They overexpress Arg-Gly-Asp (RGD) binding integrin receptors that play crucial roles in cell proliferation and stemness through interaction with the extracellular matrix. Here, we showed that monodisperse polymeric tadpole nanoparticles covalently coupled with different RGD densities regulated colon CSC proliferation and stemness in a RGD density-dependent manner. These tadpoles penetrated deeply and evenly into tumor spheroids and specifically entered cells with cancer stem markers CD24 and CD133. Low RGD density tadpoles triggered integrin α5 expression that further activated TGF-ß3 and TGF-ß2 signaling pathways, confirmed by the increase of pERK and Bcl-2 protein levels. This process is associated with the RGD cluster presentation controlled by the RGD density on the tadpole surface.
Assuntos
Proliferação de Células , Células-Tronco Neoplásicas , Oligopeptídeos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Animais , Nanoestruturas/química , Linhagem Celular Tumoral , Nanopartículas/químicaRESUMO
Porcine circovirus 2 (PCV2) infection is one of the most serious threats to the swine industry. While the disease can be prevented, to some extent, by commercial PCV2a vaccines, the evolving nature of PCV2 necessitates the development of a novel vaccine that can compete with the mutations of the virus. Thus, we have developed novel multiepitope vaccines based on the PCV2b variant. Three PCV2b capsid protein epitopes, together with a universal T helper epitope, were synthesized and formulated with five delivery systems/adjuvants: complete Freund's adjuvant, poly(methyl acrylate) (PMA), poly(hydrophobic amino acid), liposomes and rod-shaped polymeric nanoparticles built from polystyrene-poly(N-isopropylacrylamide)-poly(N-dimethylacrylamide). Mice were subcutaneously immunized with the vaccine candidates three times at three-week intervals. All vaccinated mice produced high antibody titters after three immunizations as analyzed by the enzyme-linked immunosorbent assay (ELISA), while mice vaccinated with PMA-adjuvanted vaccine elicited high antibody titers even after a single immunization. Thus, the multiepitope PCV2 vaccine candidates designed and examined here show strong potential for further development.
Assuntos
Circovirus , Doenças dos Suínos , Vacinas Virais , Suínos , Animais , Camundongos , Anticorpos Antivirais , Doenças dos Suínos/prevenção & controle , Peptídeos , Epitopos , Adjuvantes ImunológicosRESUMO
We rationally designed a monomer that when polymerized formed a well-defined nonionic polymer [poly(2-(methacryloyloxy) ethylureido glycinamide), PMEGA] by reversible addition fragmentation chain transfer with a flat and tunable upper critical solution temperature (UCST) in water. The monomer was made in one pot from commercially available compounds and with ease of purification. Strong hydrogen-bonding side groups on the polymer produced sharp coil-to-globule transitions upon cooling below its UCST. Ideal random copolymers produced with butyl methacrylate also showed flat UCST profiles, in which the UCST increased with a greater butyl methacrylate copolymer composition from 7 to 65 °C. In the presence of NaCl, the UCST decreased linearly with NaCl concentration due to the "salting-in" effect, and it was found that the slopes from the linear decrease of UCST were nearly identical for all copolymer compositions. This new polymer and its copolymers support the hypothesis that strong hydrogen bonding between the side groups allowed the flat UCST to be readily tuned with a high level of predictability. We postulate that this polymer system may provide wide biological applicability similar to that found for the well-used flat lower critical solution temperature (LCST) of poly(N-isopropylacrylamide).
Assuntos
Polímeros , Água , Micelas , Polimerização , TemperaturaRESUMO
Continued SARS-CoV-2 transmission among the human population has meant the evolution of the virus to produce variants of increased infectiousness and virulence, coined variants of concern (VOCs). The last wave of pandemic infections was driven predominantly by the delta VOC, but because of continued transmission and adaptive mutations, the more highly transmissible omicron variant emerged and is now dominant. However, due to waning immunity and emergence of new variants, vaccines alone cannot control the pandemic. The application of an antiviral coating to high-touch surfaces and physical barriers such as masks are an effective means to inactivate the virus and their spread. Here, we demonstrate an environmentally friendly water-borne polymer coating that can completely inactivate SARS-CoV-2 independent of the infectious variant. The polymer was designed to target the highly glycosylated spike protein on the virion surface and inactivate the virion by disruption of the viral membrane through a nano-mechanical process. Our findings show that, even with low amounts of coating on the surface (1 g/m2), inactivation of alpha, delta, and omicron VOCs and degradation of their viral genome were complete. Furthermore, our data shows that the polymer induces little to no skin sensitization in mice and is non-toxic upon oral ingestion in rats. We anticipate that our transparent polymer coating can be applied to face masks and many other surfaces to capture and inactivate the virus, aiding in the reduction of SARS-CoV-2 transmission and evolution of new variants of concern.
Assuntos
COVID-19 , SARS-CoV-2 , Animais , COVID-19/prevenção & controle , Humanos , Camundongos , Polímeros , Ratos , SARS-CoV-2/genética , VírionRESUMO
Anisotropic Janus ("snowman") nanoparticles with a single protrusion are currently made via the solvent swelling-induced method. Here, we demonstrate without the aid of toxic solvents a generally applicable method for the formation of anisotropic polymer nanoparticles directly in water by controlling polymer mobility through tuning its glass transition temperature (Tg ). Spherical structures, formed immediately after the emulsion polymerization, transformed into uniform tadpoles (with head diameter ≈60â nm and tail length ≈130â nm) through the protrusion of a single cylindrical tail when cooled to a temperature above the Tg of the polymer. Cooling the spheres to below the Tg produced kinetically trapped kettlebell structures that could be freeze-dried and rehydrated without any structural change. These unique kettlebells could transform into uniform tadpoles by heating above the Tg , representing a triggered and on-demand structural reorganization.
RESUMO
Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non-proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell toward stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.
Assuntos
Células-Tronco NeoplásicasRESUMO
Biological macromolecules such as proteins and nucleic acids are monodisperse just as low-molar-mass organic compounds are. However, synthetic macromolecules contain mixtures of different chain lengths, the most uniform being generated by living polymerizations, which exhibit a maximum of 1-3% of chains with the desired length. Monodisperse natural and synthetic oligomers can be obtained in low quantities by tedious, multistep iterative methods. Here we report a methodology to synthesize monodisperse synthetic macromolecules by self-interrupted living polymerization. This methodology relies on a concept that combines supramolecular and macromolecular chemistry and differs from the conventional reactivity principles employed in the synthesis of polymers for over 100 years.
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This special issue of Biomacromolecules highlights research from The International Polymer Colloid Group (IPCG), which was founded in 1972 as a forum for the exchange of ideas and emerging research activities for scientists and engineers from both academia and industry who study or use polymer colloids. The increasing relevance of polymeric structures with colloidal dimensions to biomacromolecules research provided the impetus for organizing this special issue. The IPCG is composed of over 120 researchers from over 20 countries who are elected to membership. Activities comprise annual symposia including a biennial International Polymer Colloid Group Research Conference and a semiannual newsletter that incorporates a summary of recent (including unpublished) research results from our members.
Assuntos
Coloides , PolímerosRESUMO
Polymer nanostructures can be designed with tailored properties and functions by varying their shape, chemical compositions, and surface functionality. The poor stability of these soft materials in solvent other than water can be overcome by introducing cross-links. However, cross-linking complex morphologies remains a challenge. Here, by using the temperature-directed morphology transformation method, we show that the symmetric (nanoworm) and asymmetric (tadpole) nanostructure cores can be UV-cross-linked through the coupling of styrene and para-chlorostyrene units found in the core by irradiating at 254 nm for up to 5 h. Once cross-linked, these nanostructures maintain their structure in organic solvent, further allowing us to couple on a water-insoluble pro-fluorescent probe with high efficiency.
Assuntos
Nanoestruturas/química , Polímeros/química , Resinas Acrílicas/química , Cromatografia em Gel , Química Click , Difusão Dinâmica da Luz , Corantes Fluorescentes/química , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Polimerização , Solventes/química , Estirenos/química , Propriedades de Superfície , Temperatura , Raios UltravioletaRESUMO
Targeted delivery of therapeutic drugs using nanoparticles to the highly aggressive triple negative breast cancer cells has the potential to reduce side effects and drug resistance. Cell entry into triple negative cells can be enhanced by incorporating cell binding receptor molecules on the surface of the nanoparticles to enhance receptor-mediated entry pathways, including clatherin or caveolae endocytosis. However, for highly aggressive cancer cells, these pathways may not be effective, with the more rapid and high volume uptake from macropinocytosis or phagocytosis being significantly more advantageous. Here we show, in the absence of attached cell binding receptor molecules, that asymmetric polymer tadpole nanostructure coated with a thermoresponsive poly(N-isopropylacrylamide) polymer with approximately 50% of this polymer in a globular conformation resulted in both high selectivity and rapid uptake into the triple breast cancer cell line MDA-MB-231. We found that the poly(N-isopropylacrylamide) surface coating in combination with the tadpole's unique shape had an almost 15-fold increase in cell uptake compared to spherical particles with the same polymer coating, and that the mode of entry was most likely through phagocytosis. Delivery of the tadpole attached with doxorubicin (a prodrug, which can be released at pHs < 6) showed a remarkable 10-fold decrease in the IC50 compared to free doxorubicin. It was further observed that cell death was primarily through late apoptosis, which may allow further protection from the body's own immune system. Our results demonstrate that by tuning the chemical composition, polymer conformation and using an asymmetric-shaped nanoparticle, both selectivity and effective delivery and release of therapeutics can be achieved, and such insights will allow the design of nanoparticles for optimal cancer outcomes.
Assuntos
Nanopartículas , Nanoestruturas , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Larva , Polímeros , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Conventional self-assembly methods of block copolymers in cosolvents (i.e., usually water and organic solvents) has yet to produce a pure and monodisperse population of nanocubes. The requirement to assemble a nanocube is for the second block to have a high molecular weight. However, such high molecular weight block copolymers usually result in the formation of kinetically trapped nanostructures even with the addition of organic cosolvents. Here, we demonstrate the rapid production of well-defined polymer nanocubes directly in water by utilizing the thermoresponsive nature of the second block (with 263 monomer units), in which the block copolymer was fully water-soluble below its lower critical solution temperature (LCST) and would produce a pure population of nanocubes when heated above this temperature. Incorporating a pH-responsive monomer in the second block allowed us to control the size of the nanocubes in water with pH and the LCST of the block copolymer. We then used the temperature and pH responsiveness to create an adaptive system that changes morphology when using a unique fuel. This fuel (H2O2 + MnO2) is highly exothermic, and the solution pH increases with the consumption of H2O2. Initially, a nonequilibrium spherical nanostructure formed, which transformed over time into nanocubes, and by controlling the exotherm of the reaction, we controlled the time for this transformation. This block copolymer and the water-only method of self-assembly have provided some insights into designing biomimetic systems that can readily adapt to the environmental conditions.
Assuntos
Micelas , Polímeros , Peróxido de Hidrogênio , Compostos de Manganês , Óxidos , Temperatura , ÁguaRESUMO
The mixed-ligand system consisting of tris(2-aminoethyl)amine (TREN) and tris(2-dimethylaminoethyl)amine (Me6-TREN) during the Cu(0) wire-catalyzed single electron transfer-living radical polymerization (SET-LRP) of methyl acrylate (MA) in "programmed" biphasic mixtures of the dipolar aprotic solvents NMP, DMF, and DMAc with H2O is reported. Kinetic and chain end analysis studies by NMR and MALDI-TOF before and after thio-bromo "click" reaction demonstrated that Me6-TREN complements and makes the less expensive TREN a very efficient ligand in the absence of externally added Cu(II)Br2. Statistical analysis of the kinetic data together with control experiments demonstrated that this mixed-ligand effect enhanced the apparent rate constant of propagation, monomer conversion, and molecular weight control. The most efficient effect was observed at a 1/1 molar ratio between these two ligands, suggesting that in addition to a fast exchange between the two ligands, a new single dynamic ligand generated by hydrogen bonding may be responsible for the mixed ligand observed.
Assuntos
Cobre/química , Etilenodiaminas/química , Polimerização , Catálise , Cinética , Ligantes , Espectroscopia de Ressonância Magnética , Polimetil Metacrilato/química , Solventes/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Água/químicaRESUMO
The ability of cancer cells to form clusters is a characteristic feature in the development of metastatic tumours with drug resistance. Several studies demonstrated that clusters of circulating tumour cells (CTCs) have a greater metastatic potential to establish new tumours at secondary sites than single CTCs. However, the mechanism of cluster formation is not well understood. In this study, we investigated whether cancer stemness would contribute to cluster formation. We used a tumour sphere culture method to enrich cancer stem cells (CSCs) from colon cancer cells and found that during the second generation of sphere culture, clusters (between 3 and 5 cells) formed within the first 24 hours, whereas the rest remained as single cells. The clusters were analysed for stemness and metastatic potential, including gene expressions for cancer stemness (CD133 and Lgr5), epithelial-mesenchymal transition (E-cadherin and TGF-ß 1-3) and hypoxia-induced factors (HIF-1α and HIF-2α). The results showed that the clusters expressed higher levels of these genes and colon CSC surface markers (including CD24, CD44 and CD133) than the single cells. Among these markers, CD24 seemed the major contributor linking the cells into the clusters. These clusters also showed a stronger ability to both form colonies and migrate. Our data collectively suggest that colon cancer stemness contributes to cluster formation and that clustered cells exhibit a great metastatic potential. Our study thus provides a method to study the CTC clusters and derive insight into oncogenesis and metastasis.
Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Neoplasias do Colo/metabolismo , Células-Tronco Neoplásicas/metabolismo , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Fenótipo , Esferoides CelularesRESUMO
BACKGROUND: Programmed cell death ligand 1 (PD-L1) is an important immune-inhibitory protein expressed on cancer cells to mediate cancer escape through interaction with PD-1 expressed on activated T lymphocytes (T cells). Previously, we reported that colon and breast cancer stem cells (CSCs) expressed much higher levels of PD-L1 than their parental cells, suggesting they will be more resistant to immune attack. METHODS: We investigated the underlining mechanism of PD-L1 increase in colon CSCs, with a special focus on the effect of insulin and epithelial growth factor (EGF), the two fundamental components to sustain the metabolism and stemness in the culture of CSCs. RESULTS: We found that insulin increased the total and surface PD-L1 levels through PI3K/Akt/mTOR pathway as the increase could be inhibited by the dual inhibitor of the pathway, BEZ235. EGF didn't affect the total PD-L1 levels of CSCs but increased the cell surface protein levels by flow cytometry analysis, indicating EGF promotes the transport of PD-L1 to the cell surface. Blocking cell surface PD-L1 with a specific antibody resulted in a significant reduction of tumour sphere formation but didn't interfere with the sphere growth, suggesting that cell surface PD-L1 may act as an adhering molecule for CSCs. CONCLUSIONS: Apart from the essential roles in metabolism and stemness, insulin and EGF involve in up-regulation of PD-L1 expression in colon CSCs, therefore the inhibition of insulin and EGF/EGFR pathways can be considered for cancer immunotherapy or combined with PD-1/PD-L1 antibody-based cancer immunotherapy to eliminate CSCs.
Assuntos
Antígeno B7-H1/metabolismo , Neoplasias do Colo/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Insulina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Membrana Celular/metabolismo , Neoplasias do Colo/terapia , Citoplasma/metabolismo , Células HT29 , Humanos , Imidazóis/farmacologia , Imunoterapia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/farmacologia , Regulação para CimaRESUMO
Targeting the spleen with nanoparticles could increase the efficacy of vaccines and cancer immunotherapy, and have the potential to treat intracellular infections including leishmaniasis, trypanosome, splenic TB, AIDS, malaria, and hematological disorders. Although, nanoparticle capture in both the liver and spleen has been well documented, there are only a few examples of specific capture in the spleen alone. It is proposed that the larger the nanoparticle size (>400 nm) the greater the specificity and capture within the spleen. Here, we synthesized five nanostructures with different shapes (ranging from spheres, worms, rods, nanorattles, and toroids) and poly( N-isopropylacrylamide), PNIPAM, surface coating using the temperature-directed morphology transformation (TDMT) method. Globular PNIPAM (i.e., water insoluble) surface coatings have been shown to significantly increase cell uptake and enhanced enzyme activity. We incorporated a globular component of PNIPAM on the nanostructure surface and examined the in vivo biodistribution of these nanostructures and accumulation in various tissues and organs in a mouse model. The in vivo biodistribution as a function of time was influenced by the shape and PNIPAM surface composition, in which organ capture and retention was the highest in the spleen. The rods (â¼150 nm in length and 15 nm in width) showed the highest capture and retention of greater than 35% to the initial injection amount compared to all other nanostructures. It was found that the rods specifically targeted the cells in the red pulp region of the spleen due to the shape and PNIPAM coating of the rod. This remarkable accumulation and selectively into the spleen represents new nanoparticle design parameters to develop new splenotropic effects for vaccines and other therapeutics.
Assuntos
Resinas Acrílicas/química , Nanopartículas/química , Animais , Feminino , Temperatura Alta , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/metabolismo , Nanopartículas/ultraestrutura , Células RAW 264.7 , Baço/metabolismo , Polímeros Responsivos a Estímulos/química , Distribuição TecidualRESUMO
Inspired by the many reported successful applications of DNA-encoded chemical libraries in drug discovery projects with protein targets, we decided to apply this platform to nucleic acid targets. We used a 120-billion-compound set of 33 distinct DNA-encoded chemical libraries and affinity-mediated selection to discover binders to a panel of DNA targets. Here, we report the successful discovery of small molecules that specifically interacted with DNA G-quartets, which are stable structural motifs found in G-rich regions of genomic DNA, including in the promoter regions of oncogenes. For this study, we chose the G-quartet sequence found in the c-myc promoter as a primary target. Compounds enriched using affinity-mediated selection against this target demonstrated high-affinity binding and high specificity over DNA sequences not containing G-quartet motifs. These compounds demonstrated a moderate ability to discriminate between different G-quartet motifs and also demonstrated activity in a cell-based assay, suggesting direct target engagement in the cell. DNA-encoded chemical libraries and affinity-mediated selection are uniquely suited to discover binders to targets that have no inherent activity outside of a cellular context, and they may also be of utility in other nucleic acid structural motifs.
Assuntos
DNA/química , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Ressonância de Plasmônio de SuperfícieRESUMO
Polymer nanostructures can be designed with specific properties and functions, such as controlled shape, size, chemical composition, and adaptive ability to change shape or size in response to environmental cues. Precise control to organize polymer chains into uniform nonspherical symmetric and asymmetric nanostructures and at scale remains a synthetic challenge. Here, by using the temperature-directed morphology transformation (TDMT) method we show through a systematic organization of polymer chains the synthesis of well-defined asymmetric (i.e., tadpole) and symmetric (i.e., worm) nanostructures in water at high polymer concentrations. This method further allowed the production of tadpoles with controlled and uniform tail lengths, ranging from 200 to 800 nm. The organization of chains could be driven by environmental conditions to produce adaptive nanostructure systems.
Assuntos
Nanoestruturas/química , Polímeros/química , Água/química , Polímeros/síntese química , TemperaturaRESUMO
Cyclic polymers with internal constraints provide new insight into polymer properties in solution and bulk and can serve as a model system to explain the stability and mobility of cyclic biomacromolecules. The model system used in this work consisted of cyclic polystyrene structures, all with a nearly identical molecular weight, designed with 0-3 constraints located at strategic sites within the cyclic polymer, with either 4 or 6 branch points. The total number of branch points (or arms) within the cyclic ranged from 0 to 18. Molecular dynamic (MD) simulations showed that as the number of arms increased within the cyclic structure, the radius of gyration and the hydrodynamic radius generally decreased, suggesting the greater number of constraints resulted in a more compact polymer chain. The simulations further showed that the excluded volume was much greater for the cyclics compared to a linear polymer at the same molecular weight. The spirocyclic, a structure consisting of three rings joined in series, showed significant excluded volume effects in agreement with experimental data; the reason for which is unclear at this stage. Interestingly, under a size exclusion chromatography flow, the radius of hydration for all the cyclic structures increased compared with the DLS data, and could be explained from the greater swelling of the rings perpendicular to the flow found from previous simulations on rings. This data suggests that the greater compactness, greater excluded volume and structural rearrangements under flow of constrained cyclic polymers could be used to provide a physical basis for understanding greater stability and activity of cyclic biological macromolecules.
Assuntos
Simulação de Dinâmica Molecular , Polímeros/química , Estrutura MolecularRESUMO
The oxidation potential of a test set of 21 nitroxide radicals, including a number of novel compounds, has been studied experimentally in acetonitrile and correlated with theoretical calculations. It was found that both Hammett constants (σp) of the substituents on the nitroxide radicals and hyperfine splitting constants of the respective nitrogen atoms (αN) were well correlated to their experimental oxidation potentials. Theoretical calculations, carried out at the G3(MP2,CC)(+)//M06-2X/6-31+G(d,p) level of theory with PCM solvation corrections, were shown to reproduce experiments to within a mean absolute deviation of 33 mV, with a maximum deviation of 64 mV. The oxidation potentials of the nitroxides examined varied over 400 mV, depending on ring size and substitution. This considerable variation can be rationalised by the ability of various substituents to electrostatically stabilize the oxidised oxoammonium cation. Importantly, this can be quantified by a simple predictive relationship involving the distance scaled dipole and quadrupole moments of the analogous cyclohexyl ring. This highlights the often-overlooked role of through-space electrostatic substituent effects, even in formally neutral compounds.