Resolution of 9,10-Diketo[7]helicene and Its Use in One-Step Preparation of Helicene-Based D-A-D Push-Pull Systems.

Racemic 9,10-diketo[7]helicene was successfully separated into enantiomers using a reversible and stereoselective reaction with 2,2'-diamino-1,1'-binaphthalene with moderate yields but with remarkable purity (>99% de). The enantiomerically pure diketone was used as a convenient starting material for the preparation of helicene-based push-pull molecules, which incorporated aza-aryl acceptors and diarylaminophenylene donor groups in a single step. A series of six push-pull systems, along with three reference molecules without donors, were prepared and studied using UV/vis and fluorescence measurements, circular dichroism, and DFT calculations.

Phytocannabinoids and gingival inflammation: Preclinical findings and a placebo-controlled double-blind randomized clinical trial with cannabidiol.

OBJECTIVE: The aim of this study was to: (1) evaluate the anti-inflammatory effects of cannabidiol (CBD) on primary cultures of human gingival fibroblasts (HGFs) and (2) to clinically monitor the effect of CBD in subjects with periodontitis. BACKGROUND: The use of phytocannabinoids is a new approach in the treatment of widely prevalent periodontal disease. MATERIALS AND METHODS: Cannabinoid receptors were analyzed by western blot and interleukin production detected using enzyme immunoassay. Activation of the Nrf2 pathway was studied via monitoring the mRNA level of heme oxygenase-1. Antimicrobial effects were determined by standard microdilution and 16S rRNA screening. In the clinical part, a placebo-control double-blind randomized study was conducted (56 days) in three groups (n = 90) using dental gel without CBD (group A) and with 1% (w/w) CBD (group B) and corresponding toothpaste (group A - no CBD, group B - with CBD) for home use to maintain oral health. Group C used dental gel containing 1% chlorhexidine digluconate (active comparator) and toothpaste without CBD. RESULTS: Human gingival fibroblasts were confirmed to express the cannabinoid receptor CB2. Lipopolysaccharide-induced cells exhibited increased production of pro-inflammatory IL-6 and IL-8, with deceasing levels upon exposure to CBD. CBD also exhibited antimicrobial activities against Porphyromonas gingivalis, with an MIC of 1.5 µg/mL. Activation of the Nrf2 pathway was also demonstrated. In the clinical part, statistically significant improvement was found for the gingival, gingival bleeding, and modified gingival indices between placebo group A and CBD group B after 56 days. CONCLUSIONS: Cannabidiol reduced inflammation and the growth of selected periodontal pathogenic bacteria. The clinical trial demonstrated a statistically significant improvement after CBD application. No adverse effects of CBD were reported by patients or observed upon clinical examination during the study. The results are a promising basis for a more comprehensive investigation of the application of non-psychotropic cannabinoids in dentistry.

Hepatic biotransformation of non-psychotropic phytocannabinoids and activity screening on cytochromes P450 and UDP-glucuronosyltransferases.

This study examined the biotransformation of phytocannabinoids in human hepatocytes. The susceptibility of the tested compounds to transformations in hepatocytes exhibited the following hierarchy: cannabinol (CBN) > cannabigerol (CBG) > cannabichromene (CBC) > cannabidiol (CBD). Biotransformation included hydroxylation, oxidation to a carboxylic acid, dehydrogenation, hydrogenation, dehydration, loss/shortening of alkyl, glucuronidation and sulfation. CBN was primarily metabolized by oxidation of a methyl to a carboxylic acid group, while CBD, CBG and CBC were preferentially metabolized by direct glucuronidation. The study also screened for the activity of recombinant human cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs), which could catalyze the hydroxylation and glucuronidation of the tested compounds, respectively. We found that CBD was hydroxylated mainly by CYPs 2C8, 2C19, 2D6; CBN by 1A2, 2C9, 2C19 and 2D6; and CBG by 2B6, 2C9, 2C19 and 2D6. CBC exhibited higher susceptibility to CYP-mediated transformation than the other tested compounds, mainly with CYPs 1A2, 2B6, 2C8, 2C19, 2D6 and 3A4 being involved. Further, CBD was primarily glucuronidated by UGTs 1A3, 1A7, 1A8, 1A9 and 2B7; CBN by 1A7, 1A8, 1A9 and 2B7; CBG by 1A3, 1A7, 1A8, 1A9, 2B4, 2B7 and 2B17; and the glucuronidation of CBC was catalyzed by UGTs 1A1, 1A8, 1A9 and 2B7.

Synthesis of Aza[n]helicenes (n = 4-7) via Photocyclodehydrochlorination of 1-Chloro-N-aryl-2-naphthamides.

A series of aza[n]helicenes (n = 4-7) was synthesized using a photocyclodehydrochlorination of 1-chloro-N-aryl-2-naphthamides as a general synthetic procedure introducing the nitrogen atom to the third ring of the helicene framework. The effect of the nitrogen presence in the helicene skeleton on the physicochemical properties of the prepared aza[n]helicenes was studied and compared to those of the parent carbo-analogues. The insertion of a nitrogen atom into the outer edge of the helicene molecule has a severe impact on certain physicochemical properties such as optical rotation, electrostatic potentials, and intermolecular interactions. On the other hand, some other properties such as UV/vis, fluorescence, and phosphorescence spectra remained almost unaffected when compared to the parent carbohelicenes. A nitrogen atom can be also used for further derivatization, which can lead to further modification of helicene properties, as manifested here in the fluorescence changes induced by protonation.

Synthesis of Aza[n]phenacenes (n = 4-6) via Photocyclodehydrochlorination of 2-Chloro-N-aryl-1-naphthamides.

A novel methodology for the synthesis of aza[n]phenacenes was successfully developed utilizing photocyclodehydrochlorination reaction of 2-chloro-N-aryl-1-naphthamides. In these key intermediates, the factors influencing the photoreaction were studied. The target aza[n]phenacenes were obtained by triflation or chlorination from prepared phenanthridinones, followed by hydrogenation. The introduction of a nitrogen atom into a phenacene skeleton induced changes in the physicochemical properties. The important properties of prepared aza[n]phenacenes (n = 4-6) were studied experimentally and by density functional theory calculations and were compared to those of their carbo analogues. Furthermore, some important features of the crystalline aza[n]phenacenes were investigated, including intermolecular interaction in the crystal lattice and the increased solubility or decreased melting points.

Enantioenriched Ruthenium-Tris-Bipyridine Complexes Bearing One Helical Bipyridine Ligand: Access to Fused Multihelicenic Systems and Chiroptical Redox Switches.

The synthesis and photophysical and chiroptical properties of novel aza[n]helicenes (6a-d, 10a,b, n = 4-7) substituted with one or two 2-pyridyl groups are described. The preparation was performed via an adapted Mallory reaction using aromatic imines as precursors. The obtained novel class of helical 2,2'-bipyridine ligands was then coordinated to Ru(bipy)22+ units, thus affording the first diastereomerically and enantiomerically pure [RuL(bipy)2]2+ (11a,c, L = 6a,c) or [Ru2L'(bipy)4]4+ (12, L' = 10b) complexes. The topology and stereochemistry of these novel metal-based helical architectures were studied in detail, notably using X-ray crystallography. Interestingly, the coordination to ruthenium(II) enabled the preparation of fused multihelical systems incorporating aza- and ruthena-helicenes within the same scaffold. The photophysical, chiroptical, and redox properties of these complexes were examined in detail, and efficient redox-triggered chiroptical switching activity was evidenced.

Photochemical Functionalization of Helicenes.

Herein, a visible-light photochemical approach for practical helicene functionalization at very mild reaction conditions is described. The photochemical reactions allow for the regiospecific and innate late-stage functionalization of helicenes and are easily executed either through the activation of C(sp2 )-Br bonds in helicenes using K2 CO3 as inorganic base or direct C(sp2 )-H helicene bond functionalization under oxidative photoredox reaction conditions. Overall, using these transformations six different functional groups are introduced to the helicene scaffold through C-C and four different C-heteroatom bond-forming reactions.

Recent Advances in Functionalizations of Helicene Backbone.

Helicenes, chiral members of the family of polyaromatic hydrocarbons, have been increasingly used in a variety of applications in recent years. Despite their intriguing properties, wider utilization is hindered by difficult functionalization of its skeleton, which would provide access to finely tuned derivatives of desired properties. Herein, the recent advancements in the field of helicene functionalization are discussed with an emphasis on different types of transformations, their versatility, and regioselectivity.

Oxidative Photocyclization of Aromatic Schiff Bases in Synthesis of Phenanthridines and Other Aza-PAHs.

The oxidative photocyclization of aromatic Schiff bases was investigated as a potential method for synthesis of phenanthridine derivatives, biologically active compounds with medical applications. Although it is possible to prepare the desired phenanthridines using such an approach, the reaction has to be performed in the presence of acid and TEMPO to increase reaction rate and yield. The reaction kinetics was studied on a series of substituted imines covering the range from electron-withdrawing to electron-donating substituents. It was found that imines with electron-withdrawing substituents react one order of magnitude faster than imines bearing electron-donating groups. The 1H NMR monitoring of the reaction course showed that a significant part of the Z isomer in the reaction is transformed into E isomer which is more prone to photocyclization. The portion of the Z isomer transformed showed a linear correlation to the Hammett substituent constants. The reaction scope was expanded towards synthesis of larger aromatic systems, namely to the synthesis of strained aromatic systems, e.g., helicenes. In this respect, it was found that the scope of oxidative photocyclization of aromatic imines is limited to the formation of no more than five ortho-fused aromatic rings.

Preparation and Physicochemical Properties of [6]Helicenes Fluorinated at Terminal Rings.

The first racemization-stable helicene derivatives fluorinated at terminal rings, 1,2,3,4-tetrafluoro[6]helicene (6) and 1,2,3,4,13,14,15,16-octafluoro[6]helicene (15), were synthesized via the Wittig reaction followed by oxidative photocyclization in an overall yield of 41% of 6 and 76% of 15. The changed electronic structure in fluorinated helicenes was reflected in a slight shift of UV-vis absorption, fluorescence excitation, and emission spectra maxima when compared to unsubstituted [6]helicene. Cyclic voltammetry revealed a moderate decrease in the HOMO-LUMO gap with increasing fluorination. The specific rotation of tetrafluoro[6]helicene 6 enantiomers was found to be approximately 25% lower than that of unsubstituted [6]helicene. The theoretical study of the racemization barrier suggested a reasonable shift toward higher energy with increasing fluorination. The increasing fluorination also significantly affected the intermolecular interactions in the crystal lattice. The observed CH···F interactions led to the formation of 1D-molecular chains in the crystal structures of both fluorinated helicenes.

2-Bromo[6]helicene as a Key Intermediate for [6]Helicene Functionalization.

The synthesis of 2-bromo[6]helicene was revised and improved up to 51% yield. Its reactivity was thoroughly investigated, and a library of 17 different carbon, boron, nitrogen, phosphorus, oxygen and sulfur substituted derivatives was prepared. The racemization barrier for 2-bromo[6]helicene was determined, and the usage of enantiomers in the synthesis of optically pure helicenes was rationalized. The three most energy-demanding reactions using enantiomerically pure 2-bromo[6]helicene were tested in order to confirm the predicted enantiomeric excess.

Internal dynamics in helical molecules studied by X-ray diffraction, NMR spectroscopy and DFT calculations.

The conformational behaviour of a prototype helical molecule, [6]helicene, and its derivatives was studied in solution and the solid state. Available crystal structures of [6]helicene revealed surprisingly large flexibility of this molecule and variable-temperature NMR experiments provided unusual temperature dependence of chemical shifts of hydrogen, carbon and fluorine atoms in the peripheral aromatic rings of [6]helicene and tetrafluoro[6]helicene. These chemical shift changes were interpreted as a consequence of the helicene 'pitch' opening with elevated temperature, and the experimental data were corroborated by DFT calculations of the chemical shift dependence on the helicene conformation and by variable-temperature DFT molecular dynamics simulations.

Synthesis and characterization of a helicene-based imidazolium salt and its application in organic molecular electronics.

Herein we demonstrate the synthesis of a helicene-based imidazolium salt. The salt was prepared by starting from racemic 2-methyl[6]helicene, which undergoes radical bromination to yield 2-(bromomethyl)[6]helicene. Subsequent treatment with 1-butylimidazole leads to the corresponding salt 1-butyl-3-(2-methyl[6]helicenyl)-imidazolium bromide. The prepared salt was subsequently characterized by using NMR spectroscopy and X-ray analysis, various optical spectrometric techniques, and computational chemistry tools. Finally, the imidazolium salt was immobilized onto a SiO2 substrate as a crystalline or amorphous deposit. The deposited layers were used for the development of organic molecular semiconductor devices and the construction of a fully reversible humidity sensor.

Home care safety markers: a scoping review.

Safety in home care is a new research frontier, and one in which demand for services continues to rise. A scoping review of the home care literature on chronic obstructive pulmonary disease and congestive heart failure was thus completed to identify safety markers that could serve to develop our understanding of safety in this sector. Results generated seven safety markers: (a) Home alone; (b) A fixed agenda in a foreign language; (c) Strangers in the home; (d) The butcher, the baker, the candlestick maker; (e) Medication mania; (f) Out of pocket: The cost of caring at home; and (g) My health for yours: Declining caregiver health.

Safety assessment and redox status in rats after chronic exposure to cannabidiol and cannabigerol.

Cannabidiol (CBD) and cannabigerol (CBG) are the two main non-psychotropic phytocannabinoids with high application potential in drug development. Both substances are redox-active and are intensively investigated for their cytoprotective and antioxidant action in vitro. In this study, we focused on an in vivo safety evaluation and the effect of CBD and CBG on the redox status in rats in a 90-d experiment. The substances were administered orogastrically in a dose of 0.66 mg synthetic CBD or 0.66 mg/1.33 mg CBG/kg/day. CBD produced no changes in the red or white blood count or biochemical blood parameters in comparison to the control. No deviations in the morphology or histology of the gastrointestinal tract and liver were observed. After 90 d of CBD exposure, a significant improvement in redox status was found in the blood plasma and liver. The concentration of malondialdehyde and carbonylated proteins was reduced compared to the control. In contrast to CBD, total oxidative stress was significantly increased and this was accompanied by an elevated level of malondialdehyde and carbonylated proteins in CBG-treated animals. Hepatotoxic (regressive changes) manifestations, disruption in white cell count, and alterations in the ALT activity, level of creatinine and ionized calcium were also found in CBG-treated animals. Based on liquid chromatography-mass spectrometry analysis, CBD/CBG accumulated in rat tissues (in the liver, brain, muscle, heart, kidney and skin) at a low ng level per gram. Both CBD and CBG molecular structures include a resorcinol moiety. In CBG, there is an extra dimethyloctadienyl structural pattern, which is most likely responsible for the disruption to the redox status and hepatic environment. The results are valuable to further investigation of the effects of CBD on redox status and should contribute towards opening up critical discussion on the applicability of other non-psychotropic cannabinoids.

Hexahelicene DNA-binding: Minor groove selectivity, semi-intercalation and chiral recognition.

In this contribution, we focused on a fundamental study targeting the interaction of water-soluble [6]helicene derivative 1 (1-butyl-3-(2-methyl[6]helicenyl)-imidazolium bromide) with double-stranded (ds) DNA. A synthetic 30-base pair duplex, plasmid, chromosomal calf thymus and salmon DNA were investigated using electrochemistry, electrophoresis and spectroscopic tools supported by molecular dynamics (MD) and quantum mechanical approaches. Both experimental and theoretical work revealed the minor groove binding of 1 to the dsDNA. Both the positively charged imidazole ring and hydrophobic part of the side chain contributed to the accommodation of 1 into the dsDNA structure. Neither intercalation into the duplex DNA nor the stable binding of 1 to single-stranded DNA were found in topoisomerase relaxation experiments with structural components of 1, i.e. [6]helicene (2) and 1-butyl-3-methylimidazolium bromide (3), nor by theoretical calculations. Finally, the binding of optically pure enantiomers (P)-1 and (M)-1 was studied using circular dichroism spectroscopy, isothermal titration calorimetry and UV Resonance Raman (UVRR) methods. Using MD and quantum mechanical methods, minor groove and semi-intercalation were proposed for compound 1 as the predominant binding modes. From the UVRR findings, we also can conclude that 1 tends to preferentially interact with adenine and guanine residues in the structure of dsDNA.

Nurses' perceptions of and responses to morally distressing situations.

Research on moral distress has paid limited attention to nurses' responses and actions. In a survey of nurses' perceptions of moral distress and ethical climate, 292 nurses answered three open-ended questions about situations that they considered morally distressing. Participants identified a range of situations as morally distressing, including witnessing unnecessary suffering, being forced to provide care that compromised values, and negative judgments about patients. They linked these situations to contextual constraints such as workload and described responses, including feeling incompetent and distancing themselves from patients. Participants described considerable effort to effect change, calling into question the utility of defining moral distress as an "inability to act due to institutional constraints" or a "failure to pursue a right course of action." Various understandings of moral distress operated, and action was integral to their responses. The findings suggest further conceptual work on moral distress and effort to support system-level change.

Framing the issues: moral distress in health care.

Moral distress in health care has been identified as a growing concern and a focus of research in nursing and health care for almost three decades. Researchers and theorists have argued that moral distress has both short and long-term consequences. Moral distress has implications for satisfaction, recruitment and retention of health care providers and implications for the delivery of safe and competent quality patient care. In over a decade of research on ethical practice, registered nurses and other health care practitioners have repeatedly identified moral distress as a concern and called for action. However, research and action on moral distress has been constrained by lack of conceptual clarity and theoretical confusion as to the meaning and underpinnings of moral distress. To further examine these issues and foster action on moral distress, three members of the University of Victoria/University of British Columbia (UVIC/UVIC) nursing ethics research team initiated the development and delivery of a multi-faceted and interdisciplinary symposium on Moral Distress with international experts, researchers, and practitioners. The goal of the symposium was to develop an agenda for action on moral distress in health care. We sought to develop a plan of action that would encompass recommendations for education, practice, research and policy. The papers in this special issue of HEC Forum arose from that symposium. In this first paper, we provide an introduction to moral distress; make explicit some of the challenges associated with theoretical and conceptual constructions of moral distress; and discuss the barriers to the development of research, education, and policy that could, if addressed, foster action on moral distress in health care practice. The following three papers were written by key international experts on moral distress, who explore in-depth the issues in three arenas: education, practice, research. In the fifth and last paper in the series, we highlight key insights from the symposium and the papers in the series, propose to redefine moral distress, and outline directions for an agenda for action on moral distress in health care.

Synthesis of 2-Phospha[7]helicene, a Helicene with a Terminal Phosphinine Ring.

A synthetic strategy toward phosphahelicenes containing a terminal phosphinine ring has been explored. The 4-phenyl-6-methyl-2-phospha[7]helicene was prepared from starting 2-bromobenzo[c]phenanthrene in 12% overall yield in 12 steps. The synthetic approach involves introduction of the phosphorus function prior to photocyclization forming the final helicene skeleton, followed by the formation of a phosphorus hexacycle. The structure of the first phosphahelicene with a terminal phosphinine ring was confirmed by X-ray crystallography.

Cannabidiol and periodontal inflammatory disease: A critical assessment.

Cannabidiol (CBD), a non-psychotropic cannabinoid produced by the genus Cannabis, is a phytoceutical that activates the endocannabinoid system (ECS) through binding to CB1 and CB2 receptors. The ECS is involved in cellular homeostasis and regulates metabolic processes in virtually all mammalian tissues. Published studies on CBD focus, inter alia, on its use in prophylaxis and as an anti-inflammatory agent. Here the authors present a critical assessment of the effects of CBD on inflammatory periodontal diseases caused by bacterial virulence factors, and evaluate critically the possible benefits and drawbacks of CBD use in dentistry. Particular attention is paid to the interaction of CBD with microbially colonized oral tissues, the inflammatory response in relation to the immune response, and the destruction/regeneration of hard and soft tissues of the periodontium.