To control three-dimensional (3D) cell spheroid formation, it is well-known the surface physicochemical and mechanical properties of cell culture materials are important; however, the formation and function of 3D cells are still unclear. This study demonstrated the precise control of the formation of 3D cells and 3D cell functions using diblock copolymers containing different ratios of a zwitterionic trimethylamine N-oxide group. The diblock copolymers were composed of poly(n-butyl methacrylate) (PBMA) as the hydrophobic unit for surface coating on a cell culture dish and stabilization in water, and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) as the precursor of N-oxide. The zwitterionic N-oxide converted from 0 to 100% using PDMAEMA. The wettability and surface zeta potential varied with different ratios of N-oxide diblock copolymer-coated surfaces, and the amount of protein adsorbed in the cell culture medium decreased monotonically with increasing N-oxide ratio. 3D cell spheroid formations were observed by seeding human umbilical cord mesenchymal stem cells (hUC-MSCs) in diblock copolymer-coated flat-bottom well plates, and the N-oxide ratio was over 40%. The cells proliferated in two-dimensions (2D) and did not form spheroids when the N-oxide ratio was less than 20%. Interestingly, the expression of undifferentiated markers of hUC-MSCs was higher on surfaces that adsorbed proteins to some extent and formed 50-150 μm spheroids in the range of 40-70% of N-oxide ratio. We revealed that a moderately protein-adsorbed surface allows precise control of spheroid formation and undifferentiated 3D cells and has potential applications for high-quality spheroids in regenerative medicine and drug screening.

Biofouling is a great challenge for engineering material in medical-, marine-, and pharmaceutical-related applications. In this study, a novel trimethylamine N-oxide (TMAO)-analog monomer, 3-(2-methylacrylamido)-N,N-dimethylpropylamine N-oxide (MADMPAO), was synthesized and applied for the grafting of poly(MADMPAO) (pMPAO) brushes on quartz crystal microbalance (QCM) chips by the combination of bio-inspired poly-dopamine (pDA) and surface-initiated atom transfer radical polymerization technology. The result of ion adsorption exhibited that a sequential pDA and pMPAO arrangement from the chip surface had different characteristics from a simple pDA layer. Ion adsorption on pMPAO-grafted chips was greatly inhibited at low salt concentrations of 1 and 10 mmol/L due to strong surface hydration in the presence of charged N+ and O- of zwitterionic pMPAO brushes on the outer layer on the chip surface, well known as the \"anti-polyelectrolyte\" effect. During BSA adsorption, pMPAO grafting also led to a marked decrease in frequency shift, indicating great inhibition of protein adsorption. It was attributed to weaker BSA-pMPAO interaction. In this study, the Au@pDA-4-pMPAO chip with the highest coating concentration of DA kept stable dissipation in BSA adsorption, signifying that the chip had a good antifouling property. The research provided a novel monomer for zwitterionic polymer and demonstrated the potential of pMPAO brushes in the development and modification of antifouling materials.

The sphingosine-1-phosphate receptor 1 (S1PR1) radiotracer [11C]CS1P1 has shown promise in proof-of-concept PET imaging of neuroinflammation in multiple sclerosis (MS). Our HPLC radiometabolite analysis of human plasma samples collected during PET scans with [11C]CS1P1 detected a radiometabolite peak that is more lipophilic than [11C]CS1P1. Radiolabeled metabolites that cross the blood-brain barrier complicate quantitative modeling of neuroimaging tracers; thus, characterizing such radiometabolites is important. Here, we report our detailed investigation of the metabolite profile of [11C]CS1P1 in rats, nonhuman primates, and humans. CS1P1 is a fluorine-containing ligand that we labeled with C-11 or F-18 for preclinical studies; the brain uptake was similar for both radiotracers. The same lipophilic radiometabolite found in human studies also was observed in plasma samples of rats and NHPs for CS1P1 labeled with either C-11 or F-18. We characterized the metabolite in detail using rats after injection of the nonradioactive CS1P1. To authenticate the molecular structure of this radiometabolite, we injected rats with 8 mg/kg of CS1P1 to collect plasma for solvent extraction and HPLC injection, followed by LC/MS analysis of the same metabolite. The LC/MS data indicated in vivo mono-oxidation of CS1P1 produces the metabolite. Subsequently, we synthesized three different mono-oxidized derivatives of CS1P1 for further investigation. Comparing the retention times of the mono-oxidized derivatives with the metabolite observed in rats injected with CS1P1 identified the metabolite as N-oxide 1, also named TZ82121. The MS fragmentation pattern of N-oxide 1 also matched that of the major metabolite in rat plasma. To confirm that metabolite TZ82121 does not enter the brain, we radiosynthesized [18F]TZ82121 by the oxidation of [18F]FS1P1. Radio-HPLC analysis confirmed that [18F]TZ82121 matched the radiometabolite observed in rat plasma post injection of [18F]FS1P1. Furthermore, the acute biodistribution study in SD rats and PET brain imaging in a nonhuman primate showed that [18F]TZ82121 does not enter the rat or nonhuman primate brain. Consequently, we concluded that the major lipophilic radiometabolite N-oxide [11C]TZ82121, detected in human plasma post injection of [11C]CS1P1, does not enter the brain to confound quantitative PET data analysis. [11C]CS1P1 is a promising S1PR1 radiotracer for detecting S1PR1 expression in the CNS.

The title compound, C11H10N2O2S2, crystallizes with one complete mol-ecule in the asymmetric unit. In the crystal, weak hydrogen bonding is observed between the N-oxide moieties and several C-H units.

Our work in the area of synthesis of metal-organic frameworks (MOFs) based on organic N-oxides led to the crystallization of pyridine-4-carboxamidoxime N-oxide. Herein we report the first crystal structure of the title compound, C6H7N3O2 [systematic name: (Z)-4-(N\'-hy-droxy-carbamimido-yl)pyridine N-oxide]. The hy-droxy-carbamimidoyl group is essentially coplanar with the aromatic ring, r.m.s.d. = 0.112 Å. The compound crystallizes in hydrogen-bonding layers built from the formation of strong O-H⋯O hydrogen bonds between the oxime oxygen atom and the oxygen atom of the N-oxide, and the formation of N-H⋯O hydrogen bonds between one amine nitro-gen atom and the N-oxide oxygen atom. These combined build R 3 4(24) ring motifs in the crystal. The crystal structure has no π-π inter-actions.

A smart fluorescence \"turn-on\" probe which contained a dansyl amide fluorophore and an N-oxide group was designed based on the bioorthogonal decaging reaction between N-oxide and the boron reagent. The reaction proceeds in a rapid kinetics (k2 =57.1±2.5 m-1  s-1 ), and the resulting reduction product showcases prominent fluorescence enhancement (up to 72-fold). Time dependent density functional theoretical (TD-DFT) calculation revealed that the process of photoinduced electron transfer (PET) from the N-oxide moiety to the dansyl amide fluorophore accounts for the quenching mechanism of N-oxide. This probe also showed high selectivity over various nucleophilic amino acids and good biocompatibility in physiological conditions. The successful application of the probe in HaloTag protein labeling and HepG2 live-cell imaging proves it a valuable tool for visualization of biomolecules.

N-oxides of N-heteroaromatic compounds find widespread applications in various fields of chemistry. Although the strictly planar aromatic structure of 1,10-phenanthroline (phen) is expected to induce unique features of the corresponding N-oxides, so far the potential of these compounds has not been explored. In fact, appropriate procedure has not been reported for synthesizing these derivatives of phen. Now, we provide a straightforward method for the synthesis of a series of mono-N-oxides of 1,10-phenanthrolines. The parent compounds were oxidized by a green oxidant, peroxomonosulfate ion in acidic aqueous solution. The products were obtained in high quality and at good to excellent yields. A systematic study reveals a clear-cut correlation between the basicity of the compounds and the electronic effects of the substituents on the aromatic ring. The UV spectra of these compounds were predicted by DFT calculations at the TD-DFT/TPSSh/def2-TZVP level of theory.

The conformation of the title compound, C13H11NO2, is partially determined by a strong, intra-molecular O-H⋯O hydrogen bond. The crystal packing consists of strongly corrugated layers parallel to the ac plane and associated through C-H⋯π(ring) inter-actions. A Hirshfeld surface analysis of the crystal structure indicates that the most significant contributions to the crystal packing are from H⋯H (44.1%), C⋯H/H⋯C (29.4%) and O⋯H/H⋯O (17.3%) contacts.

One new aporphine, dicentrine-β-N-oxide (1), together with five related known alkaloids dehydrodicentrine (2), predicentrine (3), N-methyllaurotetanine (4), cassythicine (5), and dicentrine (6) were isolated from the leaves of Ocotea puberula (Lauraceae). Antiprotozoal activity of the isolated compounds was evaluated in vitro against trypomastigote forms of Trypanosoma cruzi. Among the tested compounds, alkaloid 1 exhibited higher potential with EC50 value of 18.2 μM and reduced toxicity against NCTC cells (CC50 >200 μM - SI>11.0), similar to positive control benznidazole (EC50 of 17.7 μM and SI=10.7). Considering the promising results of dicentrine-β-N-oxide (1) against trypomastigotes, the mechanism of parasite death caused by this alkaloid was investigated. As observed, this compound reached the plasma membrane electric potential directly after 2 h of incubation and triggered mitochondrial depolarization, which probably leads to trypomastigote death. Therefore, dicentrine-β-N-oxide (1), reported for the first time in this work, can contribute to future works for the development of new trypanocidal agents.

Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide (5 b) was particularly remarkable in this regard as it demonstrated MIC90 values below 0.28 μM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b, with excellent potency against the replicating and drug-resistant strains of M. tuberculosis.