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Dermal delivery of amitriptyline for topical analgesia

Amitriptyline, administered orally, is currently one of the treatment options for the management of neuropathic pain and migraine. Because of the physicochemical properties of the molecule, amitriptyline is also a promising candidate for delivery as a topical analgesic. Here we report the dermal delivery of amitriptyline from a range of simple formulations. The first stage of the work required the conversion of amitriptyline hydrochloride to the free base form as confirmed by nuclear magnetic resonance (NMR). Distribution coefficient values were measured at pH 6, 6.5, 7, and 7.4. Solubility and stability of amitriptyline were assessed prior to conducting in vitro permeation and mass balance studies. The compound demonstrated instability in phosphate-buffered saline (PBS) dependent on pH. Volatile formulations comprising of isopropyl alcohol (IPA) and isopropyl myristate (IPM) or propylene glycol (PG) were evaluated in porcine skin under finite dose conditions. Compared with neat IPM, the IPM:IPA vehicles promoted 8-fold and 5-fold increases in the amount of amitriptyline that permeated at 24 h. Formulations containing PG also appear to be promising vehicles for dermal delivery of amitriptyline, typically delivering higher amounts of amitriptyline than the IPM:IPA vehicles. The results reported here suggest that further optimization of topical amitriptyline formulations should be pursued towards development of a product for clinical investigational studies.Graphical abstract

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings.

N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. "set" and "setting"), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings. We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants. We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band. Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

β-Trioxopyrrocorphins: pyrrocorphins of graded aromaticity.

Octaethyltrioxopyrrocorphins unexpectedly show macrocycle-aromatic properties, even though they contain the macrocyclic π-system of the non-aromatic pyrrocorphins (hexahydroporphyrins). Two of the four possible triketone regioisomers were first reported in 1969 by one-pot oxidation of octaethylporphyrin but remained essentially unexplored since. We detail here the targeted preparation of the remaining two triketone isomers and the optical and NMR spectroscopic properties of all isomers. All four regioisomers possess unique electronic properties, including broadly varying degrees of diatropicity that were experimentally determined using 1H NMR spectroscopy and computationally verified. Structural patterns modulating the aromaticity were recognized. These differences highlight the regioisomerically differentiated influences of the three β-oxo-functionalities. We also present the solid state structure of the two most common isomers (in their free base form or as zinc complexes), allowing further conclusions to be made about the resonance structures present in these triketones. Remarkably, also, the halochromic properties of the triketones differ sharply from those of regular (hydro)porphyrins, providing further support for the proposed 16-membered, 18 π-electron aromatic ring-current. The work conceptually expands the understanding of tris-modified hydroporphyrinoid analogues and the factors that enable and control porphyrinoid aromaticity.

A structural parameter to link molecular geometry to macroscopic orientation in discotic liquid crystals: study of metalloporphyrin tapes

Novel liquid crystalline (LC) molecules were prepared from a dimeric porphyrin tape. A series of metal complexes (1Zn, 1Pd, 1Cu, and 1Ni) and the free-base form (12H) of the porphyrin tape formed a columnar LC phase. Although only the central metal ions were different among these compounds, 1Ni, 12H, and 1Cu aligned homeotropically in a sandwiched glass cell, while 1Zn and 1Pd exhibited a random orientation at a macroscopic scale. The strength of the π-π interactions, tunable by the distortion of the porphyrin cores through metallation, is a key factor for the observed macroscopic orientation difference.

169. AT-752, an Oral Guanosine Nucleotide Prodrug, Exhibits Potent in Vitro Activity Against Flaviviruses and Prevents Disease Progression in a Dengue Mouse Model

BackgroundThe increasing global prevalence of human Dengue virus infection and the potential for life-threatening sequelae highlight the significance of this unmet medical need. Here we report the potent in vitro activity of AT-281, the free base form of AT-752, against Dengue virus and other flaviviruses and the in vivo efficacy of AT-752 in a mouse model of Dengue viral disease.MethodsAntiviral activities of serial dilutions of AT-281 were evaluated in infected Huh-7 cells. Effective concentrations of AT-281 required to inhibit virus yield reduction by 90% (EC90) and to prevent cytopathic effect by 50% (EC50) were determined, respectively, by visual examination and by neutral red staining, as was cytotoxicity. AG129 (α-, β- and γ-interferon knock-out) mice received an oral dose of AT‐752 (1000 mg/kg) 4 h before s.c. inoculation with Dengue virus type 2 (strain D2Y98P, 1x105 virus particles) followed by b.i.d. doses (500 mg/kg) for 7 days starting 1 h post‐inoculation (p.i.). Six groups each (n=5) of treated and control mice were scheduled to be sacrificed on days 4, 6, 7, 8, 10 and 21 p.i. with serum and spleen viral RNA levels determined by plaque assay. AT-281 efficacy was evaluated based on overall health score, survival, weight loss and viral load in serum and spleen.Results In vitro EC90 values for AT-281 against Dengue, West Nile and Yellow Fever viruses ranged from 0.26 to 0.64 µM and EC50 values for Zika and Japanese encephalitis were 0.21 and 0.64 µM, respectively (Table 1). No toxicity was observed up to the highest concentrations tested (172 µM). Oral administration of AT-752 to Dengue-infected AG129 mice substantially improved survival, prevented weight loss and lowered viral loads by day 6, with virus being undetectable on day 8 and thereafter (Figure 1). Serum and spleen viral loads in control mice declined between days 4 and 8 but no control mice survived beyond day 8. In contrast, AT-752 treated mice survived up to day 19, eventually succumbing to model-induced CNS sequelae.Table 1. Antiviral Activity of AT-281 Against Various Flaviviruses in Huh-7 Cell Cultures Figure 1. Efficacy of AT-752 in the AG129 mouse model of Dengue infection. Panel a: health score: 1, healthy; 2, coat slightly ruffled; 3, coat ruffled/wet; 4, coat very ruffled, eyes slightly closed/inset; 5, coat very ruffled, eyes closed/inset; 6, coat very ruffled, eyes closed/inset, moribund requiring humane euthanasia; 7, found dead. Panel b: Kaplan-Meier survival plot. Panel c: percent weight loss. Panel d: serum viremia. Panel e: spleen viral load. ConclusionThe potent activity of AT-281 against Dengue virus in vitro and the efficacy of its salt form, AT-752, in the terminal AG129 mouse model warrant further clinical development of the drug. Preclinical safety studies are in progress and clinical trials will be initiated thereafter.DisclosuresSteven S. Good, MS, Atea Pharmaceuticals, Inc. (Employee) Adel Moussa, PhD, Atea Pharmaceuticals, Inc. (Employee) Xiao-Jian Zhou, PhD, Atea Pharmaceuticals, Inc. (Employee) Jean-Pierre Sommadossi, PhD, Atea Pharmaceuticals, Inc. (Board Member) Keith Pietropaolo, BA, Atea Pharmaceuticals, Inc. (Employee)

1265. AT-527, an Oral Purine Nucleotide Prodrug Exhibiting Potent In Vitro Antiviral Activity Against Human Coronaviruses, Including SARS-CoV-2

BackgroundCoronaviruses (CoVs) are the causative pathogens of several human diseases, including seasonal respiratory infections (HCoV-229E and HCoV-OC43), Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV-1) and the novel CoV recently identified as the virus responsible for the current COVID-19 pandemic, SARS-CoV-2. AT-527 is currently in Phase 2 clinical trials and has demonstrated potent activity and a well-tolerated safety profile in HCV-infected subjects. Here we report the in vitro activity of AT-511, the free base form of AT-527, against SARS-CoV-2 and other CoVs.MethodsBHK-21, Huh-7, RD and differentiated normal human bronchial epithelial (dNHBE) cell cultures were exposed to virus and serial dilutions of test compounds. Independent assessments of antiviral activity were obtained by determining effective concentrations of test compounds required to 1) prevent half-maximal (EC50) virus-induced cytopathic effect (CPE) using MTT or neutral red staining and 2) produce virus yield reductions (VYR) by 90% (EC90) using standard endpoint dilution CCID50 assays in Vero 76 cells. Half maximal cytotoxicity of test compounds was determined by dye (MTT or neutral red) staining in the absence of added virus or by microscopic inspection (dNHBE cells only).ResultsTable 1 presents the in vitro activities of AT-511 against several coronaviruses. Also included in these assays are the antiviral activities of potential COVID-19 oral treatments, including chloroquine, hydroxychloroquine and N4-hydroxycytidine.Table 1. In Vitro Activity of AT-511 Against Various Human Coronaviruses ConclusionThe data demonstrate the potent in vitro activity of AT-511 against several CoVs, with individual EC90 values ranging from 0.34 to 1.2 µM against HCoV-229E, HCoV-OC43, SARS-CoV-1 and SARS-CoV-2 and less activity against MERS-CoV (average EC90 = 36 µM). The potent in vitro antiviral activity of AT-511 against SARS-CoV-2 (EC90 = 0.55 µM), associated with the AT-527 safety profile in treated HCV patients, support the ongoing clinical evaluation of the safety and efficacy of AT-527 in COVID-19 patients.DisclosuresSteven S. Good, MS, Atea Pharmaceuticals, Inc. (Employee) Adel Moussa, PhD, Atea Pharmaceuticals, Inc. (Employee) Xiao-Jian Zhou, PhD, Atea Pharmaceuticals, Inc. (Employee) Keith Pietropaolo, B.A., Atea Pharmaceuticals, Inc. (Employee) Jean-Pierre Sommadossi, PhD, Atea Pharmaceuticals, Inc. (Board Member)

Photophysical Properties and Electronic Structure of Zinc(II) Porphyrins Bearing 0-4 meso-Phenyl Substituents: Zinc Porphine to Zinc Tetraphenylporphyrin (ZnTPP).

Six zinc(II) porphyrins bearing 0-4 meso-phenyl substituents have been examined spectroscopically and theoretically. Comparisons with previously examined free base analogues afford a deep understanding of the electronic and photophysical effects of systematic addition of phenyl groups in porphyrins containing a central zinc(II) ion versus two hydrogen atoms. Trends in the wavelengths and relative intensities of the absorption bands are generally consistent with predictions from time-dependent density functional theory calculations and simulations from Gouterman's four-orbital model. These trends derive from a preferential effect of the meso-phenyl groups to raise the energy of the highest occupied molecular orbital. The calculations reveal additional insights, such as a progressive increase in oscillator strength in the violet-red (B-Q) absorption manifold with increasing number of phenyls. Progressive addition of 0-4 phenyl substituents to the zinc porphyrins in O2-free toluene engenders a reduction in the measured lifetime of the lowest singlet excited state (2.5-2.1 ns), an increase in the S1 → S0 fluorescence yield (0.022-0.030), a decrease in the yield of S1 → T1 intersystem crossing (0.93-0.88), and an increase in the yield of S1 → S0 internal conversion (0.048-0.090). The derived rate constants for S1 decay reveal significant differences in the photophysical properties of the zinc chelates versus free base forms. The unexpected finding of a larger rate constant for internal conversion for zinc chelates versus free bases is particularly exemplary. Collectively, the findings afford fundamental insights into the photophysical properties and electronic structure of meso-phenylporphyrins, which are widely used as benchmarks for tetrapyrrole-based architectures in solar energy and life sciences research.

Chiral Amphiphilic Secondary Amine-Porphyrin Hybrids for Aqueous Organocatalysis.

Two chiral proline-derived amphiphilic 5-substituted-10,15,20-tris(4-sulfonatophenyl)porphyrins were prepared, and their pH-dependent supramolecular behavior was studied. In neutral aqueous solutions, the free-base form of the hybrids is highly soluble, allowing enamine-based organocatalysis to take place, whereas under acidic conditions, the porphyrinic protonated core of the hybrid leads to the formation of self-assembled structures, so that the hybrids flocculate and their catalytic activity is fully suppressed. The low degree of chirality transfer observed for aqueous Michael and aldol reactions strongly suggests that these reactions take place under true “in water” organocatalytic conditions. The highly insoluble catalyst aggregates can easily be separated from the reaction products by centrifugation of the acidic reaction mixtures, and after neutralization and desalting, the sodium salts of the sulfonated amine-porphyrin hybrids, retaining their full catalytic activity, can be recovered in high yield.

Three new orbifloxacin multicomponent crystal forms towards pharmaceutical improvement†

Orbifloxacin (ORBI) is a third-generation synthetic fluoroquinolone used as an antimicrobial veterinary drug for the treatment of gastrointestinal and respiratory infections. Structural information about this drug is restricted to a hemihydrate containing ORBI as a zwitterion, which is the crystal form expected to be present in veterinary solid oral formations. Since the major problem with the ORBI hemihydrate form is its poor solubility and structure conservation upon dehydration, leading to uncontrollable water contents in the active pharmaceutical ingredient (API), we present here for the first time the crystal structures of three ORBI multicomponent crystal forms including two salt solvates and one cocrystal salt solvate: a hydrochloride salt monohydrate (1), a nitrate salt monohydrate (2) and a phosphoric acid hemi-cocrystal of the dihydrogen phosphate salt monohydrate (3). The latter form presents a very interesting multicomponent crystal feature having phosphate species either as a counter-ion or a neutral coformer. Pure crystalline samples of 1–3 were obtained and characterised by powder X-ray diffraction, infrared spectroscopy, thermogravimetry and differential thermal analyses. We have provided here a full analytical dataset for three new multicomponent solid forms of orbifloxacin, which may improve drug solubility and mitigate the possible drawback of inconsistent water load inherent to its hydrated free-base form.

In vitro antimicrobial effects of chlorhexidine diacetate versus chlorhexidine free base dressings

The aim of this study was to investigate the in vitro antimicrobial performance of a chlorhexidine diacetate dressing and a chlorhexidine free base dressing to determine if the free base form of chlorhexidine has the potential to be an effective alternative to the chlorhexidine salts used in conventional, chlorhexidine-based antimicrobial dressings. Dressing samples were inoculated with clinically relevant pathogenic microorganisms including Gram-positive and Gram-negative bacteria, yeasts and fungus, and subsequently evaluated for in vitro log10 reduction at 1-, 3-, and 7-day time points. Chlorhexidine mole content was also calculated as a function of dressing surface area for both sample types to allow for formulation-independent comparison between the dressings. The chlorhexidine free base dressing demonstrated >0.5 log10 superior mean antimicrobial efficacy at 67% of the experimental time points and equivalent mean antimicrobial efficacy (≤0.5 log10 different) at the remaining time points when compared with the chlorhexidine diacetate dressing. The chlorhexidine free base dressing was also found to contain 36% less chlorhexidine mole content than the chlorhexidine diacetate dressing. Our results suggest that a dressing formulated with chlorhexidine free base can deliver in vitro antimicrobial performance at both a magnitude and rate that meets or exceeds that of a chlorhexidine diacetate-based dressing, while also allowing for a reduction in total chlorhexidine content per dressing. These findings could be of particular interest to researchers developing new antimicrobial technologies as well as to infection preventionists when evaluating antimicrobial products for use on clinical patients at elevated risk of infection.

Vapor phase infrared identification of regioisomeric N-(dimethoxybenzyl)-4-iodo- and 4-bromo-2,5-dimethoxyphenethylamines

Vapor phase infrared spectroscopy provides data for the differentiation of the individual regioisomers of the six N-(dimethoxybenzyl)-4-iodo-2,5-dimethoxyphenethylamines and the six N-(dimethoxybenzyl)-4-bromo-2,5-dimethoxyphenethylamines. These compounds differ from the traditional N-(2-methoxybenzyl)-4-iodo- and 4-bromo-2,5-dimethoxyphenethylamines (25I- and 25B-NBOMe) by the addition of one methoxy group into the N-methoxybenzyl molecular framework. The vapor phase infrared spectra obtained directly as the compounds elute from the GC column provide data for the identification of any one of these regioisomeric compounds to the exclusion of the other five substances of mass spectral equivalence. The spectra are derived from the compounds in the free base form at temperatures preventing interference from water vapor, intermolecular interactions such as polymorphism or other related issues of salt form and/or relative crystallinity. Fragment ions in the electron ionization mass spectra of these compounds identify the nature of the halogen (I or Br) but not the position of substitution of the methoxy groups on the benzyl aromatic ring.These compounds are composed of two separate and distinct ring systems, the halogenated phenethylamines 4-iodo-2,5-dimethoxyphenethylamine and 4-bromo-2,5-dimethoxyphenethylamine and a second ring system consisting of the six positional isomers of dimethoxybenzylamine. Major absorption bands resulting from aromatic ring C–C and C–O stretching vibrations provide data for differentiation of the benzyl ring substitution pattern. Model compounds representing all the single ring systems provide significant structural correlation with the vapor phase infrared spectra for these regioisomeric NBOMe derivatives.

Investigation of Within-Tablet Dynamics for Extended Release of a Poorly Soluble Basic Drug from Hydrophilic Matrix Tablets Using ATR-FTIR Imaging.

Hydrophilic matrices are an effective option for oral controlled release but can face challenges in terms of bioavailability and efficacy when used in conjunction with poorly soluble, weakly basic drugs. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) imaging provides dynamic information relating to the location and chemical nature of both the sustained release matrix and the active pharmaceutical ingredient (API) during hydration/dissolution. In this study, we have identified a model system combining itraconazole (IT), a poorly soluble, weakly basic API that has pKa in the physiological range, and hydroxypropyl methylcellulose, which is a commonly used oral tablet matrix. This system was investigated to determine the swelling kinetics at different pH values at a fixed ionic strength and to facilitate the study of the influence of hydrating media pH on the drug particle movement (translocation). Using ATR-FTIR imaging, we were able to show that gel layer formation and swelling were independent of pH but highly dependent on the ionic strength of the hydrating medium in placebo tablets. When the ionic strength was fixed, gel layer formation and radial swelling were both shown to be pH-dependent when IT was incorporated into the matrix. This was verified using optical imaging. The chemical specificity of ATR-FTIR imaging permitted the observation of transformational changes of IT from the free base to the ionized form in the tablet core during hydration. This phenomenon was shown to be greater at pH 1.5 than at pH 7. ATR-FTIR imaging was able to follow drug particle translocation at both pH 1.5 and pH 7; however, the extent of migration away from the tablet core was shown to be greater at lower pH. The location of the translocated particles within the gel layer was different between the two studied pH values, with particles being located close to the swelling front at pH 7 and within the diffusion front at pH 1.5. In both pH environments, the translocated IT particles were shown to be predominantly in the free base form. No evidence of fully solubilized IT was observed in the surrounding medium because of the inherent aqueous solubility of IT being below the instrument detection limits. This work highlighted the value of utilizing a chemically specific spectroscopic tool to increase the understanding of the nature of the factors affecting the release of a pH-dependent, poorly soluble drug from a hydrophilic matrix at different pH values and permitted greater insights into what happens inside the polymer matrix during drug release.

Synthesis and Characterization of Novel Quinolyl Porphyrins as Receptors. Study of their Association with Halophenols and 4‐Nitrophenol as a Reference

In this work, new receptors built on the porphyrin scaffold were synthesized for halophenols recognition. A quinolyl group was introduced on the porphyrin's periphery as binding site, to form two series of molecules based on two distinct porphyrin frames and which were obtained in free base and zinc forms. The binding between these porphyrin‐based receptors and halophenols (2,3,4,6‐tetrachlorophenol, 2,4,6‐trichlorophenol or 2,4,6‐tribromophenol) was studied. As established by 1H NMR spectroscopy, the binding constants are in the range of two‐digit numbers, which value is correlated with the porphyrin structure (substitutive pattern, form of the free base or ZnII complex) and the pKa of the respective phenol. These data, supplemented by a X‐ray structure of one adduct complex, indicate a single interaction between the phenolic proton and the nitrogen of the quinolyl group. The binding with p‐nitrophenol was tested for comparison. The association constant increases at a scale of one order of magnitude. This net stabilization of the adduct complex in this case is explained by additional hydrogen bonds implying the nitro function, as also witnessed by X‐ray diffractometry.

Colorimetric assay for the rapid determination of free-base nicotine in e-liquid

Nicotine exists in e-liquids primarily as the monoprotonated form and free-base form. The free-base form could be evaluated by use of a water-soluble indicator.

The synthesis of a hexameric expanded hemiporphyrazine

Although the chemistry of expanded porphyrins is well developed, there has been significantly less work on expanded isoindoline based macrocycles such as hemiporphyrazines. In this report we present the synthesis and characterization of a new hexameric expanded hemiporphyrazine which we refer to as hexahemiporphyrazine. The synthesis incorporated bis(6-amino-2-pyridyl)amine as a starting material, which could be produced from 2,6-diaminopyridine using melt reaction conditions. Bis(6-amino-2-pyridyl)amine can adopt a three different conformations, two of which are observed in the free base and protonated form, and the third in the backbone of hexahemiporphyrazine. Reaction of bis(6-amino-2-pyridyl)amine and diiminoisoindoline in the presence of a catalytic amount of BF3 produces the hexihemiporphyrazine macrocycle, which was characterized spectroscopically and by X-ray crystallography. Structure elucidation reveals two inverted pyridine rings in a configuration reminiscent of that seen in hexaphyrin, however hexahemiporphyrazine lacks cross conjugation across the macrocycle.

Dithienothiophene fused 30π heptaphyrin and 34π octaphyrins: Syntheses, characterization and spectral properties

Syntheses of DTT fused 30[Formula: see text] heptaphyrin and 34[Formula: see text] octaphyrins are reported. The inclusion of fused group in the precursor itself allowed easy syntheses of these macrocycles. Fusion makes the macrocycles planar thus allowing strong [Formula: see text] electronic conjugation. Both 30[Formula: see text] heptaphyrin and 34[Formula: see text] octaphyrins are aromatic in freebase and protonated forms as revealed by large [Formula: see text] values in 1H NMR spectrum and sharp-intense Soret like bands in UV-vis spectrum. Interestingly one of the DTT ring undergoes fliping upon protonation in 34[Formula: see text] doubly fused octaphyrin. Such a large ring fliping is unprecedented in the literature. Single crystal X-ray analysis confirms planar nature of 34[Formula: see text] octaphyrins. Furthermore, the structure reveals two type of hydrogen bonding interactions: (a) CH[Formula: see text] (thiophene) and (b) CH[Formula: see text] (mesityl) leading to self assambled dimer separated by a distance of ∼3.0Å.

Nicotine in tobacco product aerosols: ‘It's déjà vu all over again’

IntroductionThe distribution of nicotine among its free-base (fb) and protonated forms in aerosolised nicotine affects inhalability. It has been manipulated in tobacco smoke and now in electronic cigarettes by the...

Preparation, Characterisation, and Topical Delivery of Terbinafine.

Terbinafine (TBF) is commonly used in the management of fungal infections of the skin because of its broad spectrum of activity. Currently, formulations containing the free base and salt form are available. However, there is only limited information in the literature about the physicochemical properties of this drug and its uptake by the skin. In this work, we conducted a comprehensive characterisation of TBF, and we also examined its percutaneous absorption in vitro in porcine skin. TBF-free base was synthesised from the hydrochloride salt by a simple proton displacement reaction. Both the free base and salt form were further analysed using Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Delivery of TBF-free base in excised porcine skin was investigated from the following solvents: Isopropyl myristate (IPM), propylene glycol monolaurate (PGML), Transcutol® (TC), propylene glycol (PG), polyethylene glycol 200 (PEG 200), oleic acid (OL), ethanol (EtOH), and isopropyl alcohol (IPA). Permeation and mass balance studies confirmed that PG and TC were the most efficacious vehicles, delivering higher amounts of TBF-free base to the skin compared with a commercial gel (p < 0.05). These preliminary results are promising and will inform the development of more complex formulations in future work.

Synthesis of Azulitriphyrins(1.2.1) and Related Benzocarbatriphyrins.

Bis(pyrrolylmethyl)azulene dialdehydes underwent intramolecular McMurry coupling, and following oxidation with DDQ and addition of trifluoroacetic acid, gave aromatic azulitriphyrin cations. The proton NMR spectra for these contracted carbaporphyrinoids showed the internal CH upfield at ca. 2 ppm, while the bridging methine units appeared downfield between 8 and 10 ppm, demonstrating that the macrocycles possess significant 14π electron diamagnetic ring currents. Although protonated azulitriphyrins(1.2.1) proved to be very stable, the free base forms were unstable and could not be isolated. Treatment of an azulitriphyrin with KOt-Bu-t-BuOOH gave rise to oxidative ring contractions that afforded the first examples of benzocarbatriphyrins. These contracted porphyrinoids also exhibit aromatic ring currents, and the internal CH resonances shifted upfield to 0.5-0.7 ppm. Protonation afforded cations with slightly enhanced diatropic properties. Nucleus independent chemical shift and anisotropy of induced current density calculations confirmed that benzocarbatriphyrins are 14π electron delocalized aromatic systems that bypass the fused arene units.

Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions.

Four distinct folding patterns are identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns are characterized by different intramolecular hydrogen bonding schemes that arise largely from different thiourea conformers. The free base forms of the catalysts are characterized by folds where the intramolecular hydrogen bonds between the urea and the thiourea units remain intact. In contrast, the catalytically relevant salt forms of the catalyst, where the catalyst forms an ion pair with the substrate or substrate analogues, appear in two entirely different folding patterns. With larger anions that mimic the dialkyl malonate substrates, the catalysts maintain their native fold both in the solid state and in solution, but with smaller halide anions (fluoride, chloride, and bromide), the catalysts fold around the halide anion (anion receptor fold), and the intramolecular hydrogen bonds are disrupted. Titration of catalyst hexafluoroacetylacetonate salt with tetra-n-butylammonium chloride results in dynamic refolding of the catalyst from the native fold to the anion receptor fold.