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A generic framework for enhancing an initial solubility prediction with ML, even with simple methods and a modestly sized, sparse dataset. We dissect the setup to show the model “locking on” to the target system as more data are made available.

A predictive tool was developed to aid process design and to rationally select optimal solvents for isolation of active pharmaceutical ingredients. The objective was to minimize the experimental work required to design a purification process by (i) starting from a rationally selected crystallization solvent based on maximizing yield and minimizing solvent consumption (with the constraint of maintaining a suspension density which allows crystal suspension); (ii) for the crystallization solvent identified from step 1, a list of potential isolation solvents (selected based on a series of constraints) is ranked, based on thermodynamic consideration of yield and predicted purity using a mass balance model; and (iii) the most promising of the predicted combinations is verified experimentally, and the process conditions are adjusted to maximize impurity removal and maximize yield, taking into account mass transport and kinetic considerations. Here, we present a solvent selection workflow based on logical solvent ranking supported by solubility predictions, coupled with digital tools to transfer material property information between operations to predict the optimal purification strategy. This approach addresses isolation, preserving the particle attributes generated during crystallization, taking account of the risks of product precipitation and particle dissolution during washing, and the selection of solvents, which are favorable for drying.

The symmetries of a crystal are notoriously uncorrelated to those of its constituent molecules. This symmetry breaking is typically thought to occur during crystallization. Here we demonstrate that one of the two symmetry elements of olanzapine crystals, an inversion centre, emerges in solute dimers extant in solution prior to crystallization. We combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations. We show that crystals grow non-classically, predominantly by incorporation of centrosymmetric dimers. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of the incorporation of dimers, which exist in equilibrium with a majority of monomers. We show that growth by dimers is preferred due to overwhelming accumulation of adsorbed dimers on the crystal surface, where it is complemented by dimerization and expedites dimer incorporation into growth sites. Crystal symmetry is notoriously uncorrelated to the symmetry of the constituent molecules that make up a crystal. Symmetry breaking is typically thought to occur during nucleation and growth, but a symmetry element of olanzapine crystals—an inversion centre—has now been shown to emerge in centrosymmetric dimers extant in solution prior to crystallization.

Silk is now making inroads into advanced pharmaceutical and biomedical applications. Both bottom-up and top-down approaches can be applied to silk and the resulting aqueous silk solution can be processed into a range of material formats, including nanoparticles. Here, we demonstrate the potential of microfluidics for the continuous production of silk nanoparticles with tuned particle characteristics. Our microfluidic-based design ensured efficient mixing of different solvent phases at the nanoliter scale, in addition to controlling the solvent ratio and flow rates. The total flow rate and aqueous : solvent ratios were important parameters affecting yield (1 mL min���1 > 12 mL min���1). The ratios also affected size and stability; a solvent : aqueous total flow ratio of 5 : 1 efficiently generated spherical nanoparticles 110 and 215 nm in size that were stable in water and had a high beta-sheet content. These 110 and 215 nm silk nanoparticles were not cytotoxic (IC50 > 100 ��g mL���1) but showed size-dependent cellular trafficking. Overall, microfluidic-assisted silk nanoparticle manufacture is a promising platform that allows control of the silk nanoparticle properties by manipulation of the processing variables.

The co-crystalline structure of the non-steroidal, anti-inflammatory indomethacin with the non-toxic, Generally Regarded As Safe (GRAS) sweetener component saccharin was investigated up to 6.33 GPa using a Diamond Anvil Cell (DAC). Single crystal X-ray diffraction measurements show that the co-crystal remains in the same triclinic, P-1, phase throughout the compression with a significant reduction in void space (155.69 to 55.61Å3). Information on the response of different types of intermolecular interactions to external force at the same time is enabled by the use of a co-crystal. We have rationalised that the length and compression rate of the saccharin amide dimer in the co-crystal is caused by the dimer sitting in a ‘pocket’ surrounded by the indomethacin framework. This framework reduces the effects of molecular packing on the dimer allowing for an ideal hydrogen bonding geometry.

Silk nanoparticles are viewed as promising vectors for intracellular drug delivery as they can be taken up into cells by endocytosis and trafficked to lysosomes, where lysosomal enzymes and the low pH trigger payload release. However, the subsequent degradation of the silk nanoparticles themselves still requires study. Here, we report the responsiveness of native and PEGylated silk nanoparticles to degradation following exposure to proteolytic enzymes (protease XIV and α-chymotrypsin) and papain, a cysteine protease. Both native and PEGylated silk nanoparticles showed similar degradation behavior over a 20 day exposure period (degradation rate: protease XIVpapain ≫ α-chymotrypsin). Within 1 day, the silk nanoparticles were rapidly degraded by protease XIV, resulting in a ∼50% mass loss, an increase in particle size, and a reduction in the amorphous content of the silk secondary structure. By contrast, 10 days of papain treatment was necessary to observe any significant change in nanoparticle properties, and α-chymotrypsin treatment had no effect on silk nanoparticle characteristics over the 20-day study period. Silk nanoparticles were also exposed ex vivo to mammalian lysosomal enzyme preparations to mimic the complex lysosomal microenvironment. Preliminary results indicated a 45% reduction in the silk nanoparticle size over a 5-day exposure. Overall, the results demonstrate that silk nanoparticles undergo enzymatic degradation, but the extent and kinetics are enzyme-specific.

Particle swelling is a crucial component in the disintegration of a pharmaceutical tablet. The swelling of particles in a tablet creates stress inside the tablet and thereby pushes apart adjoining particles, eventually causing the tablet to break-up. This work focused on quantifying the swelling of single particles to identify the swelling-limited mechanisms in a particle, i.e. diffusion- or absorption capacity-limited. This was studied for three different disintegrants (sodium starch glycolate/SSG, croscarmellose sodium/CCS, and low-substituted hydroxypropyl cellulose/L-HPC) and five grades of microcrystalline cellulose (MCC) using an optical microscope coupled with a bespoke flow cell and utilising a single particle swelling model. Fundamental swelling characteristics, such as diffusion coefficient, maximum liquid absorption ratio and swelling capacity (maximum swelling of a particle) were determined for each material. The results clearly highlighted the different swelling behaviour for the various materials, where CCS has the highest diffusion coefficient with 739.70 μm2/s and SSG has the highest maximum absorption ratio of 10.04 g/g. For the disintegrants, the swelling performance of SSG is diffusion-limited, whereas it is absorption capacity-limited for CCS. L-HPC is both diffusion- and absorption capacity-limited. This work also reveals an anisotropic, particle facet dependant, swelling behaviour, which is particularly strong for the liquid uptake ability of two MCC grades (PH101 and PH102) and for the absorption capacity of CCS. Having a better understanding of swelling characteristics of single particles will contribute to improving the rational design of a formulation for oral solid dosage forms.

Bacterial biofilm infections incur massive costs on healthcare systems worldwide. Particularly worrisome are the infections associated with pressure ulcers and prosthetic, plastic, and reconstructive surgeries, where staphylococci are the major biofilm-forming pathogens. Non-leaching antimicrobial surfaces offer great promise for the design of bioactive coatings to be used in medical devices. However, the vast majority are cationic, which brings about undesirable toxicity. To circumvent this issue, we have developed antimicrobial nanocellulose films by direct functionalization of the surface with dehydroabietic acid derivatives. Our conceptually unique design generates non-leaching anionic surfaces that reduce the number of viable staphylococci in suspension, including drug-resistant Staphylococcus aureus, by an impressive 4-5 log units, upon contact. Moreover, the films clearly prevent bacterial colonization of the surface in a model mimicking the physiological environment in chronic wounds. Their activity is not hampered by high protein content, and they nurture fibroblast growth at the surface without causing significant hemolysis. In this work, we have generated nanocellulose films with indisputable antimicrobial activity demonstrated using state-of-the-art models that best depict an "in vivo scenario". Our approach is to use fully renewable polymers and find suitable alternatives to silver and cationic antimicrobials.

Introduction Anthracyclines, such as doxorubicin, remain an important class of chemotherapeutic agent however their efficacy in treating cancer is limited by a cumulative dose-dependent cardiotoxicity. Whilst most studies have focused on cardiomyocyte impairment, circulating doxorubicin has been shown to impact human microvascular responses to doxorubicin in coronary vessels.1 Studies show increased endothelial cell permeability resulting in increased paracellular permeability due to damage to the integrity of cell-cell junctions.2 Strategies to maintain vessel integrity and prevent endothelial cell dysregulation could represent a novel therapeutic opportunity to limit the toxic effects of doxorubicin. The aim of this project was to assess the impact of doxorubicin upon endothelial gap junction proteins, in particular connexin-43 (Cx43). Methods Commercially available Human Coronary Artery Endothelial Cells (HCAEC) were used for this study. Doxorubicin intrinsic fluorescence was detected at 568 nm therefore drug uptake and accumulation in HCAECs was detected using Leica Confocal SP8 microscope using licensed Leica Application Suite X (LAS X) software. Changes in connexin protein expression were detected using Western blotting and with subcellular localisation assessed using indirect immunofluorescence (IF). Results Western blotting confirmed abundant expression of Cx43 in HCAECs with indirect fluorescence demonstrating clustering of Cx43 punctae and gap junction plaque formation. Treatment with doxorubicin (0.1–100μM, 24hrs) resulted in a concentration-dependent accumulation of drug in the nucleus. This coincided with notable subcellular redistribution of Cx43 from the membrane to cytosol, indicative of Cx43 internalisation and decreased endothelial Cx43 expression. Conclusions Doxorubicin caused internalisation of endothelial Cx43 and altered the total cellular expression levels of Cx43. The mechanism of Cx43 cellular redistribution and loss remains unknown, however the wider impact of these effects upon healthy cell-cell communication and myoendothelial gap junction activity could be a major contributing factor in doxorubicin cardiotoxicity. Whilst the actions of doxorubicin could be causing Cx43 downregulation through protein degradation, recent evidence suggests that Cx43 can be secreted in extracellular vesicles (EVs).3 Further investigation into the mechanism of aberrant Cx43 expression and potential doxorubicin-dependent Cx43 secretion through EVs will form the basis of future study. References Hader SN, et al. American Journal of Physiology-Heart and Circulatory Physiology 2019;317(4):H705– H710. doi:10.1152/ajpheart.00370.2019. Wilkinson EL, Sidaway JE, Cross MJ. Biology open 2016;5(10):1362–1370. doi:10.1242/bio.020362 Gemel J, Kilkus J, Dawson G, Beyer EC. Cancers 2019;11(4):476. doi:10.3390/cancers11040476

Oscillatory flow reactors (OFRs) are a new generation of tubular mixing and reaction equipment uniquely capable of combining continuous near plug flow with homogeneous particle suspension, yet the design of OFRs for liquid–solid and multi-phase flow processes relies on rules established during the past two decades from single, liquid-phase studies. A Design of Experiment (DoE) approach was herein implemented for establishing the relationship between four key geometrical parameters of the inner tube baffles and both the suspension of particles and the axial dispersion for liquid–solid continuous flows in 10 mm internal diameter (d) meso-scale tubes with periodic baffles. The parameters evaluated were the orifice open diameter, do = 0.35d–0.50d; the open cross section, α = 0.12d–0.25d, constriction spacing, l = 1.5d–3.0d, and baffle shape (sharp vs smooth edged). A total of ten tubes were tested, five consisting of smooth periodic constrictions (SPC) and the other five of sharp edged periodic constrictions (SEPC) according to a complete 2 × 2 factorial design with 1 central point. Each tube was experimentally evaluated via optical imaging of suspended monodispersed polyvinyl chloride (PVC) particles. Both SPC and SEPC meso-tubes were capable of delivering a near plug flow behaviour and the values of axial dispersion coefficient (Dc) estimated for the solids were in the range of 1.0–2.2 × 10−4 m2 s−1. In contrast, the minimum (critical) fluid oscillation conditions required for full suspension of particles varied significantly, in general with the SPC tubes requiring up to 50% lower amplitude for full particles suspension. Overall, α revealed the dominant parameter in controlling solids backmixing, and the inner tube geometry requiring the lowest energy input for homogenous particle suspension and minimum Dc (i.e. sharpest residence time distribution) presented a l/d = 3, do = 0.35d, α = 12% and SPC design. This study is believed to support the future design of optimised meso-scale OFR systems for continuous screening and manufacturing of value-added liquid–solid and multi-phase systems, such as catalytic and crystallisation processes.

Silk continues to amaze: over the past decade, new research threads have emerged that include the use of silk fibroin for advanced pharmaceutics, including its suitability for drug delivery. Despite this ongoing interest, the details of silk fibroin structures and their subsequent drug interactions at the molecular level remain elusive, primarily because of the difficulties encountered in modeling the silk fibroin molecule. Here, we generated an atomistic silk model containing amorphous and crystalline regions. We then exploited advanced well-tempered metadynamics simulations to generate molecular conformations that we subsequently exposed to classical molecular dynamics simulations to monitor both drug binding and release. Overall, this study demonstrated the importance of the silk fibroin primary sequence, electrostatic interactions, hydrogen bonding, and higher-order conformation in the processes of drug binding and release. �� Copyright �� 2019 American Chemical Society.

The bacterial order actinomycetales are responsible for the production of 65–70 % of microbially produced specialised metabolites with diverse biological activities, with some actinomycetale strains containing over 30 Biosynthetic Gene Clusters encoding for these metabolites. However, only approximately 10 % of these genes are typically transcribed in a mono-culture setting. Furthermore, it has been observed that microbial interactions may induce these cryptic gene clusters providing an ecological advantage to the producer strains. To understand the chemical exchange between strains isolated from the marine environment, microbial interactions were assessed using 49 actinomycetale strains, two Pseudomonas and one Bacillus strain. In total, 72 tri-cultures (three strains) were analysed resulting in 29 strains that showed an altered phenotypes as a result of the interaction. These were then evaluated in a one-to-one culture (two strains) followed by bioactivity screening. Using this data, nine tri-cultures and 27 one-to-one cultures were evaluated using tandem Mass Spectometry, enabling chemically interesting interactions to be prioritized for Time of Flight Secondary Ionisation Mass Spectometry (ToF-SIMS) analysis. ToF-SIMS enables the spatial distribution of parent ions within a sample, in this case, two bacterial strains interacting in a Petri dish. The results that will be presented demonstrate that microbial interactions induce the production of metabolites and ToF-SIMS represents an exciting strategy to study bacterial chemical ecology.

A random forest model obtained from calculated physicochemical properties of solvents and observed crystallised structures of olanzapine has for the first time enabled the prediction of different types of 3-dimensional crystal packings of olanzapine solvates. A novel olanzapine solvate was obtained by targeted crystallization from the solvent identified by the random forest classification model. The model identified van der Waals volume, number of covalent bonds and polarisability of the solvent molecules as key contributors to the 3-D crystal packing type of the solvate.

Treatment of electron deficient pyridine N-oxides with 4-nitrobenzoyl chloride and a cyclic thioether in the presence of triethylamine leads to the corresponding 2-functionalized product in up to a 74% isolated yield. The transformation can also be accomplished with alternative nitrogen containing heterocycles, including quinolines, pyrimidines, and pyrazines. To expand the scope of the transformation, diisopropyl ether can be used as the reaction medium to allow for the use of solid thioether substrates.

The objective was to test the hypothesis that obesity is associated with impaired cognitive outcomes in the pre-school years. Associations were examined between weight status at age 3-5 years and cognitive performance at age 5 years. Cognitive outcome measures were tests of Pattern Construction (visuo-spatial skills), Naming Vocabulary (expressive language skills), and Picture Similarity (reasoning skills). The sample was the UK Millennium Cohort Study (MCS; n 12,349 participants). Boys with obesity at 3 years had significantly lower performance in Pattern Construction at age 5 years compared to those of a healthy weight, even after controlling for confounders (β= -0.029, p=0.03). Controlling for confounders, boys who developed obesity between the age of 3 and 5 years had lower scores in Pattern Construction (β=-0.03, p=0.03). ’Growing out’ of obesity had a beneficial impact on Picture Similarity performance in girls (β=0.03, p=0.04). Obesity in the pre-school years was associated with poorer outcomes for some cognitive measures in this study. Stronger relationships between obesity and cognition or educational attainment may emerge later in childhood.

A random forest model has for the first time enabled the prediction of the crystallisability (crystals vs. no crystals) of organic molecules with ∼70% accuracy. The predictive model is based on calculated molecular descriptors and published experimental crystallisation propensities of a library of substituted acylanilides.

A dataset consisting of structures and aqueous solubility and melting point data for 51 salt forms of the phenylethylamine base methylephedrine is presented. Analysis showed correlation between solubility and melting point and between melting point of the salt and melting point of the parent acid, but no correlation of salt solubility with solubility of the parent acid. Identification of associations was aided by examining chemically sensible subgroups of the dataset, and this approach highlighted significantly different relationships between solubility and melting point for these subgroups. Thus, for example, the expected negative correlation between solubility and melting point was found for 24 anhydrous benzoate salts, but a positive correlation observed for 8 halide salts. Hydrated forms were anomalous. Packing analysis identified groups of structures that were isostructural with respect to cation packing. Correlation between solubility and melting point was found to be greatest within these isostructural groups, implying a role for packing structure in determining solubility.

The aim of this article is to describe and compare adherence and persistence with maintenance therapies in patients with asthma or chronic obstructive pulmonary disease (COPD) in the United Kingdom (UK). A retrospective prescribing database cohort was obtained from 44 general practitioner surgeries in National Health Service Forth Valley Scotland. Patients with physician-diagnosed asthma or COPD who received maintenance therapy between January 2008 and December 2009 were included. Five classes of therapy were assessed: inhaled corticosteroids, long-acting beta-agonists, combination therapy inhalers, theophyllines and long-acting muscarinic antagonists. Adherence was calculated using the medication possession ratio (MPR) and persistence was determined using Kaplan-Meier survival analysis for the time to discontinuation (TTD) over 1 year. Two step-wise logistic regressions were performed to assess the contribution of diagnosis to adherence/persistence. A total of 13,322 patients were included in the analysis: 10,521 patients with asthma and 2801 patients with COPD. 25.2% of medication episodes for asthma and 45.6% of medication episodes for COPD were classified as having an adequate medication supply (MPR of 80-120%). The overall median TTD was 92 days (IQR, interquartile range: 50-186 days) for patients with asthma and 116 days (IQR: 58-259 days, comparison p < 0.001) for patients with COPD. Patients with COPD were found to be more likely to achieve an MPR of at least 80% (OR: 1.27, 95% CI: 1.15-1.40), but had a similar likelihood of persistence at 1 year to patients with asthma. Adherence and persistence with respiratory therapies in the UK is relatively low. There is suggestion that patients with COPD may display more adherent behaviours than patients with asthma.

The crystal structures of loxapine succinate [systematic name: 4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-1-methylpiperazin-1-ium 3-carboxypropanoate], C18H19ClN3O+·C4H5O4−, and loxapine succinate monohydrate {systematic name: bis[4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-1-methylpiperazin-1-ium] succinate succinic acid dihydrate}, 2C18H19ClN3O+·C4H4O42−·C4H6O4·2H2O, have been determined using X-ray powder diffraction and single-crystal X-ray diffraction, respectively. Fixed cell geometry optimization calculations using density functional theory confirmed that the global optimum powder diffraction derived structure also matches an energy minimum structure. The energy calculations proved to be an effective tool in locating the positions of the H atoms reliably and verifying the salt configuration of the structure determined from powder data. Crystal packing analysis of these structures revealed that the loxapine succinate structure is based on chains of protonated loxapine molecules while the monohydrate contains dispersion stabilized centrosymmetric dimers. Incorporation of water molecules within the crystal lattice significantly alters the molecular packing and protonation state of the succinic acid.

Background: The British guideline on the management of asthma produced by the British Thoracic Society (BTS) and the Scottish Intercollegiate Guidelines Network (SIGN) describes five steps for the management of chronic asthma. Combination therapy of a long-acting β2-agonist (LABA) and an inhaled corticosteroid (ICS) is recommended as first-line therapy at step 3, although the dose of ICS at which to add a LABA is subject to debate. Aims: To classify the inhaled therapy prescribed to patients with asthma in NHS Forth Valley according to two interpretations of the BTS/SIGN guideline and to evaluate the use of combination therapy in this population. Methods: A retrospective analysis including patients from 46 general practitioner surgeries was conducted. Patients with physician-diagnosed asthma were classified according to the BTS/SIGN guideline based on treatment prescribed during 2008. Patient characteristics were evaluated for the overall step classification, and specifically for therapy in step 3. Results: 12,319 patients were included. Guideline interpretation resulted in a shift of 9.2% of patients (receiving medium-dose ICS alone) between steps 2 and 3. The largest proportion of patients (32.3%) was classified at step 4. Age, sex, smoking status, chronic obstructive pulmonary disease co-morbidity, and utilisation of short-acting β2-agonists and oral corticosteroids all correlated with step; however, no differences in these characteristics were evident between low-dose combination therapy and medium-dose ICS alone at step 3. Conclusions: Further studies are needed to evaluate prescribing decisions in asthma. Guideline recommendations regarding the use of ICS dose escalation versus combination therapy need to be clarified relative to the published evidence.

An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are respo...

Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. This paper describes the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of preclinical and clinical development for drug delivery applications.

Silk is a promising biopolymer for biomedical and pharmaceutical applications due to its outstanding mechanical properties, biocompatibility and biodegradability, as well its ability to protect and subsequently release its payload in response to a trigger. While silk can be formulated into various material formats, silk nanoparticles are emerging as promising drug delivery systems. Therefore, this article covers the procedures for reverse engineering silk cocoons to yield a regenerated silk solution that can be used to generate stable silk nanoparticles. These nanoparticles are subsequently characterized, drug loaded and explored as a potential anticancer drug delivery system. Briefly, silk cocoons are reverse engineered first by degumming the cocoons, followed by silk dissolution and clean up, to yield an aqueous silk solution. Next, the regenerated silk solution is subjected to nanoprecipitation to yield silk nanoparticles – a simple but powerful method that generates uniform nanoparticles. The silk nanoparticles are characterized according to their size, zeta potential, morphology and stability in aqueous media, as well as their ability to entrap a chemotherapeutic payload and kill human breast cancer cells. Overall, the described methodology yields uniform silk nanoparticles that can be readily explored for a myriad of applications, including their use as a potential nanomedicine.

Retrospective prescribing data were obtained from 46 general practice surgeries in NHS Scotland. Patients with asthma who were naïve to previous long-acting β agonist therapy and initiated combination inhaler therapy in 2008-2009 were classified according to the inhaled corticosteroid (ICS) dose in their combination inhaler compared with the highest dose of ICS they received before initiation. Among the 685 patients (541 (79.0%) who had been prescribed an ICS previously), those originally on low-, medium- or high-dose ICS were changed to high-dose combination therapy in 122/250 (48.8%), 94/151 (62.3%) or 85/113 (75.2%) cases in each ICS dose category, respectively. These results suggest that evaluation of appropriate high-dose ICS prescribing in general practice is needed.

Scanning tunneling microscopy (STM) has become a staple surface microscopy technique for a number of research fields ranging from semiconductor research to heterogeneous catalysis. Pharmaceutical compounds, however, remain largely unstudied. Here we report the first STM study of carbamazepine (CBZ), an anti-epileptic drug, on Au(111) and Cu(111) surfaces. The analysis reveals that CBZ adopts unusual chiral molecular architectures on both metals. These previously unreported structures, which are strikingly different from CBZ packing arrangements observed in 3D crystal structures, indicate that the main molecular architecture is driven by a combination of CBZ intermolecular hydrogen bonding and metal-CBZ interactions. Comparison of the 2D molecular structures reveals large differences in local geometry and packing density that are dependent on the nature of the metal surface. These results have implications for the potential role of metal surfaces as heteronuclei or templating agents for controlling polymorph formation, which continues to be a problem for many compounds in the pharmaceutical industry including CBZ.

The benzo[c]phenanthridines (BCPs) are a group of compounds that are believed to express their antitumor activity through the inhibition of topoisomerase I. The enzyme is crucial to cell cycle division and progression, and regulates the equilibrium between relaxed and supercoiled DNA that occurs during DNA replication. Over the years, we have prepared a number of BCPs and employed a number of biophysical techniques to explore their mechanism of action and improve their activity against this particular enzyme. The naturally occurring alkaloid fagaronine 1 and the synthetic compound ethoxidine 3 are two of the most active compounds, although their inhibitory mechanisms are different, being a poison and suppressor, respectively. We have modified the approach of steered molecular dynamics to create a torque on the intercalator to comprehensively sample the DNA binding site, and using topoisomerase I crystal structures, have proposed a model to explain the different mechanisms of action for these two BCP compounds.

Nine organotin fluorocarboxylates R n SnO 2 CR f (n = 3, R = Bu, R f = CF 3 , C 2 F 5 , C 3 F 7 , C 7 F 15 ; R = Et, R f = CF 3 , C 2 F 5 ; R = Me, R f = C 2 F 5 ; n = 2, R = Me, R f = CF 3 ) have been synthesized; key examples have been used to deposit fluorine-doped SnO 2 thin films by atmospheric pressure chemical vapour deposition. Et 3 SnO 2 CC 2 F 5 , in particular, gives high-quality films with fast deposition rates despite adopting a polymeric, carboxylate-bridged structure in the solid state, as determined by X-ray crystallography. Gas-phase electron diffraction on the model compound Me 3 SnO 2 CC 2 F 5 shows that accessible conformations do not allow contact between tin and fluorine, and that direct transfer is therefore unlikely to be part of the mechanism for fluorine incorporation in SnO 2 films. The structure of Me 2 Sn(O 2 CCF 3 ) 2 (H 2 O) has also been determined and adopts a trans-Me 2 SnO 3 coordination sphere about tin in which each carboxylate group is monodentate.

Isopropyl-thiazole ((iPr)Th) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)(2) is bound by a short lexitropsin of sequence formyl-PyPy(iPr)Th-Dp (where Py represents N-methyl pyrrole, (iPr)Th represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT(5)AG(7)T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the (iPr)Th group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G(7) and the (iPr)Th nitrogen, which lies on the minor groove floor. The B(I)/B(II) DNA backbone equilibrium is altered at the T(5) 3'-phosphate position to accommodate a B(II) configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.

The structure of Ru(C5Me5)(C5F5) has been determined by gas-phase electron diffraction and density functional theory. Comparison structures of the known compounds Ru(C5H5)2 and Ru(C5F5)(C5H5), as well as the unknown compound Ru(C5F5)2, have also been determined by density functional theory.

This article details the exploration of perdeuterated acrylic acid at high pressure using neutron diffraction. The structural changes that occur in acrylic acid-d4 are followed via diffraction and rationalized using the Pixel method. Acrylic acid undergoes a reconstructive phase transition to a new phase at ∼0.8 GPa and remains molecular to 7.2 GPa before polymerizing on decompression to ambient pressure. The resulting product is analyzed via Raman and FT-IR spectroscopy and differential scanning calorimetry and found to possess a different molecular structure compared with polymers produced via traditional routes.

Three novel crystalline solvates of the antiepileptic compound carbamazepine were obtained by targeted crystallisation from solvents identified by a Random Forest classification of solvent properties, experimental conditions and known crystallisation outcomes.

Natural products are the most consistently successful source of drug leads, both historically and currently. Despite this, the use of natural products in industrial drug discovery has fallen out of favour. Natural products are likely to continue to be sources of new commercially viable drug leads because the chemical novelty associated with natural products is higher than that of any other source: this is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads. Areas to be covered: Current drug discovery strategies involving natural products are described in three sections: developments from traditionally used medicines, random testing of natural compounds on biological assays and use of virtual screening techniques with structures of natural products.The reader will gain an insight into the potential for natural products in current drug discovery paradigms, particularly in the value of using natural products in virtual screening approaches.Drug discovery would be enriched if fuller use was made of the chemistry of natural products.

The binding of three dinuclear platinum complexes, where the bridging ligand of the complexes is N,N0- (alkane-1,n-diyl)diisonicotinamide (n = 4, 6 or 8 for butane, hexane and octane, respectively) to the macrocycle para-sulphonatocalix[4]arene (sCX[4]) has been studied by 1H nuclear magnetic resonance (NMR) spectroscopy and molecular modelling. The NMR spectra show two important features, large upfield shifts of the methylene proton resonances of up to 1.8 ppm, which clearly places them within the shielding environment of the macrocycle’s cavity, and a loss of chemical symmetry of the metal complexes with extra resonances observed upon sCX[4] binding. Molecular models of the platinum–sCX[4] host–guest complexes show significant folding of the metal complexes’ aliphatic chain and a non-symmetrical interaction with the macrocycle. One side of the metal complexes forms three hydrogen bonds to sCX[4], whereas the opposite side of the metal complexes forms just one hydrogen bond, giving rise to the loss of chemical symmetry in the 1H NMR spectra. As the dinuclear platinum complexes are model anticancer drugs, the effect of sCX[4] binding was investigated in vitro in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-line A2780cp70. Whilst the free metal complexes are a magnitude of order more active than cisplatin in the A2780 cell line, they are all highly cross-resistant with cisplatin in the A2780cp70 line. Binding by sCX[4] has little affect on the metal complexes’ cytotoxicity in the sensitive cell line, but has a large effect in the resistant cell line. The two shortest metal complexes become less active when bound by sCX[4], whereas the longest metal complex becomes more cytotoxic.

Selecting polymers for drug encapsulation in pharmaceutical formulations is usually made after extensive trial and error experiments. To speed up excipient choice procedures, we have explored coarse-grained computer simulations (dissipative particle dynamics (DPD) and coarse-grained molecular dynamics using the MARTINI force field) of polymer–drug interactions to study the encapsulation of prednisolone (log p = 1.6), paracetamol (log p = 0.3) and isoniazid (log p = −1.1) in poly( l -lactic acid) (PLA) controlled release microspheres, as well as the encapsulation of propofol (log p = 4.1) in bioavailability enhancing quaternary ammonium palmitoyl glycol chitosan (GCPQ) micelles. Simulations have been compared with experimental data. DPD simulations, in good correlation with experimental data, correctly revealed that hydrophobic drugs (prednisolone and paracetamol) could be encapsulated within PLA microspheres and predicted the experimentally observed paracetamol encapsulation levels (5–8% of the initial drug level) in 50 mg ml −1 PLA microspheres, but only when initial paracetamol levels exceeded 5 mg ml −1 . However, the mesoscale technique was unable to model the hydrophilic drug (isoniazid) encapsulation (4–9% of the initial drug level) which was observed in experiments. Molecular dynamics simulations using the MARTINI force field indicated that the self-assembly of GCPQ is rapid, with propofol residing at the interface between micellar hydrophobic and hydrophilic groups, and that there is a heterogeneous distribution of propofol within the GCPQ micelle population. GCPQ–propofol experiments also revealed a population of relatively empty and drug-filled GCPQ particles.

The Drug Discovery Portal (DDP) is a research initiative based at the University of Strathclyde in Glasgow, Scotland. It was initiated in 2007 by a group of researchers with expertise in virtual screening. Academic research groups in the university working in drug discovery programmes estimated there was a historical collection of physical compounds going back 50 years that had never been adequately catalogued. This invaluable resource has been harnessed to form the basis of the DDP library, and has attracted a high-percentage uptake from the Universities and Research Groups internationally. Its unique attributes include the diversity of the academic database, sourced from synthetic, medicinal and phytochemists working an academic laboratories and the ability to link biologists with appropriate chemical expertise through a target-matching virtual screening approach, and has resulted in seven emerging hit development programmes between international contributors.

Drug discovery in universities is usually associated with research on drug targets and mechanisms, but more recently there have been efforts to progress from target studies to proof of concept by applying commercially focussed medicinal chemistry. This creates more opportunities for novel interactions and partnering models between academic groups and pharmaceutical companies. We present a review of coordinated, multi-institutional drug discovery operations within academia that are engaging with industry nationally and internationally and describe how the Drug Discovery Portal at the University of Strathclyde enhances the possibilities for academic drug discovery.

The authors have no support or funding to report. Background: Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings: Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the beta-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 mu g/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)thiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95 +/- 0.05 mu g/ml (2.43 +/- 0.13 mu M) but was not active against the whole cell organism. Conclusions/Significance: These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents. Publisher PDF

The utility of p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-[{PtCl(NH(3))(2)}(2)mu-dpzm](2+) (di-Pt; where dpzm=4,4'-dipyrazolylmethane) as a model complex, has been examined using (1)H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX[4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX[4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5'-guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX[4]. The cytotoxicity of free di-Pt and s-CX[4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC(50) of 100 and 60 microM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 microM, respectively). s-CX[4] displays no cytotoxicity at concentrations up to 1.5mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 x 10(4)M(-1)) means the host-guest complex is mostly disassociated at biologically relevant concentrations.

A reverse phase high performance liquid chromatography (HPLC) separation was established for profiling water soluble compounds in extracts from tea. Whole chromatograms were pre-processed by techniques including baseline correction, binning and normalisation. In addition, peak alignment by correction of retention time shifts was performed using correlation optimization warping (COW) producing a correlation score of 0.96. To extract the chemically relevant information from the data, a variety of chemometric approaches were employed. Principle component analysis (PCA) was used to group the tea samples according to their chromatographic differences. Three principal components (PCs) described 78% of the total variance after peak alignment (64% before) and analysis of the score and loading plots provided insight into the main chemical differences between the samples. Finally, PCA, support vector machines (SVMs) and random forest (RF) machine learning methods were evaluated comparatively on their ability to predict unknown tea samples using models constructed from a predetermined training set. The best predictions of identity were obtained by using RF.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for chromone derivatives against HIV-1 protease using molecular field analysis (MFA) with genetic partial least square algorithms (G/PLS). Three different alignment methods: field fit, pharmacophore-based, and receptor-based were used to derive three MFA models. All models produced good predictive ability with high cross-validated r(2) (r(2) (cv)), conventional r(2), and predictive r(2)(r(2)(pred)) values. The receptor-based MFA showed the best statistical results with r(2) (cv) = 0.789, r(2)= 0.886, and r(2)(pred) = 0.995. The result obtained from the receptor-based model was compared with the docking simulation of the most active compound 21 in this chromone series to the binding pocket of HIV-1 protease (PDB entry 1AJX). It was shown that the MFA model related well with the binding structure of the complex and can provide guidelines to design more potent HIV-1 protease inhibitors.

Propolis is a widely used natural remedy and a range of biological activities have been attributed to it. The chemical composition of propolis is highly variable and its quality is often controlled on the basis of one or two marker compounds. In order to progress towards a method for the quality control of this complex material, HPLC and 1H-NMR approaches as methods of quality control have been compared. HPLC analyses of 43 samples of propolis were carried out and six marker compounds were quantified in each sample. The same samples were analysed using 1H-NMR and the spectra were then converted into their first derivative forms and digitised using the software application MestRe-C. The digitised data were subjected to principal component analysis using the software application Simca-P. It was found that the chemical composition of propolis mapped well according to the geographical origins of the samples studied when the first three principal components were used to display them. In addition, each sample was assessed for anti-oxidant activity, and the results were then overlaid onto the sample groupings according to 1H-NMR data. It was observed that anti-oxidant properties also mapped quite well according to geographical origin.

The structures of 1,3,5-trisilylbenzene and hexasilylbenzene in the gas phase have been determined by electron diffraction, and that of 1,3,5-trisilylbenzene by X-ray crystallography. The structures of three trisilylbenzene isomers, three tetrasilylbenzenes, pentasilylbenzene and hexasilylbenzene have been computed, ab initio and using Density Functional Theory, at levels up to MP2/6-31G*. The primary effect of silyl substituents is to narrow the ring angle at the substituted carbon atoms. Steric interactions between silyl groups on neighbouring carbon atoms lead first to displacement of these groups away from one another, and then to displacement out of the ring plane, with alternate groups moving to opposite sides of the ring. In the extreme example, hexasilylbenzene, the SiCCSi dihedral angle is 17.8(8) degrees .

Perfluoroalkytin compounds R((4-n))Sn(R-f)(n) (R = Me, Et, Bu, R-f = C4F9, n = 1; R = Bu, R-f = C4F9, n = 2, 3;R = Bu, R-f = C6F13, n = 1) have been synthesized, characterized by H-1, C-13, F-19 and Sn-119 NMR, and evaluated as precursors for the atmospheric pressure chemical vapour deposition of fluorine-doped SnO2 thin films. All precursors were sufficiently volatile in the range 84-136 degrees C and glass substrate temperatures of ca 550 degrees C to yield high-quality films with ca 0.79-2.02% fluorine incorporation, save for Bu3SnC6F13, which incorporated < 0.05% fluorine. Films were characterized by X-ray diffraction, scanning electron microscopy, thickness, haze, emissivity, and sheet resistance. The fastest growth rates and highest quality films were obtained from Et3SnC4F9. An electron diffraction study of Me3SnC4F9 revealed four conformations, of which only the two of lowest abundance showed close F center dot center dot center dot Sri contacts that could plausibly be associated with halogen transfer to tin, and in each case it was fluorine attached to either the gamma- or delta-carbon atoms of the R-f chain. Copyright (c) 2005 John Wiley P Sons, Ltd.

The molecular structure of tetra-tert-butyldiphosphine has been determined in the gas phase by electron diffraction using the new DYNAMITE method and in the crystalline phase by X-ray diffraction. Ab initio methods were employed to gain a greater understanding of the structural preferences of this molecule in the gas phase, and to determine the intrinsic P-P bond energy, using recently described methods. Although the P-P bond is relatively long [GED 226.4(8) pm; X-ray 223.4(1) pm] and the dissociation energy is computed to be correspondingly small (150.6 kJ mol(-1)), the intrinsic energy of this bond (258.2 kJ mol(-1)) is normal for a diphosphine. The gaseous data were refined using the new Edinburgh structure refinement program ed@ed, which is described in detail. The molecular structure of gaseous P(2)Bu(t)(4) is compared to that of the isoelectronic 1,1,2,2-tetra-tert-butyldisilane. The molecules adopt a conformation with C(2) symmetry. The P-P-C angles returned from the gas electron diffraction refinement are 118.8(6) and 98.9(6) degrees, a difference of 20 degrees, whilst the C-P-C angle is 110.3(8) degrees. The corresponding parameters in the crystal are 120.9(1), 99.5(1) and 109.5(1) degrees. There are also large deformations within the tert-butyl groups, making the DYNAMITE analysis for this molecule extremely important.

The molecular structures of 1-bromo-pentaborane(9) and 2-bromo-pentaborane(9) in the gas phase have been determined by electron diffraction and ab initio and DFT computational methods. Computational methods have also been applied to the fluoro and chloro analogues, to 1,2-dibromo-pentaborane(9), and to the parent unsubstituted borane. The electronic effects of halogen substitution on the borane cage are remarkably small, particularly for chlorine and bromine substituents, and steric effects are also minimal, even in the compound with two bromine atoms. The largest effects are (a) lengthening of B((base))-B((apex)) bonds adjacent to the halogen in the 2-isomers, with an associated shortening of the opposite base-apex bond, (b) shortening of the B((base))-B((apex)) bond in the 1-fluoro compound, and (c) increase of the B((base))-B((apex))-F angle in 1-F-B(5)H(8), but a decrease in this angle in the 2-bromo compounds.