Structure and reactivity of selected organic inclusion compounds

Includes bibliographical references.The inclusion behaviour of the two host compounds 1,1 ,6,6-tetraphenylhexa-2,4- diyne-l,6-diol and cyclotriveratrylene (2,3,7,8,12,13-hexamethoxy-5,lO-dihydro- 15H-tribenzo[ a,d,g]cyclononene) was studied. Small organic guests were complexed with these hosts and their crystal structures determined. The stability and reactivity of these inclusion compounds were investigated. Kinetics of desolvation were determined for some of the inclusion compounds using both isothermal and non-isothermal methods. Rate laws were proposed and activation energies established. The selectivity of the host 1,1 ,6,6-tetraphenylhexa-2,4-diyne- 1,6-diol for certain guests was determined by competition experiments. Lattice energies were calculated in some cases. Solid state reactions were performed with the host 1,1 ,6,6-tetraphenylhexa-2,4-diyne-1 ,6-diol and selected solid guests. The resultant complexes were analysed using X-ray powder diffraction. Guest exchange reactions were also performed and the reactions were monitored either by differential scanning calorimetry or thermogravimetry. The structures of the inclusion compounds were reconciled with their physico-chemical properties

Desorption kinetics of a xanthenol-dioxane clathrate

The host xanthenol compound forms a 1:1 clathrate with dioxane, namely 9-(1-naphthyl)-9H-xanthen-9-ol–1,4-dioxane, C23H16O2·C4H8O2. The structure of this clathrate is reported, along with a study of the kinetics of desolvation and the determination of an activation energy. The guest mol­ecules are stabilized by Ohost—H⋯Oguest hydrogen bonds [O—H = 0.968 (2) Å, O⋯O = 2.7532 (13) Å and O—H⋯O = 151.9 (4)°]

DNA isolation protocol effects on nuclear DNA analysis by microarrays, droplet digital PCR, and whole genome sequencing, and on mitochondrial DNA copy number estimation.

Potential bias introduced during DNA isolation is inadequately explored, although it could have significant impact on downstream analysis. To investigate this in human brain, we isolated DNA from cerebellum and frontal cortex using spin columns under different conditions, and salting-out. We first analysed DNA using array CGH, which revealed a striking wave pattern suggesting primarily GC-rich cerebellar losses, even against matched frontal cortex DNA, with a similar pattern on a SNP array. The aCGH changes varied with the isolation protocol. Droplet digital PCR of two genes also showed protocol-dependent losses. Whole genome sequencing showed GC-dependent variation in coverage with spin column isolation from cerebellum. We also extracted and sequenced DNA from substantia nigra using salting-out and phenol / chloroform. The mtDNA copy number, assessed by reads mapping to the mitochondrial genome, was higher in substantia nigra when using phenol / chloroform. We thus provide evidence for significant method-dependent bias in DNA isolation from human brain, as reported in rat tissues. This may contribute to array "waves", and could affect copy number determination, particularly if mosaicism is being sought, and sequencing coverage. Variations in isolation protocol may also affect apparent mtDNA abundance

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Organic Salts of p-Coumaric Acid and Trans-Ferulic Acid with Aminopicolines

p-Coumaric acid (pCA) and trans-ferulic acid (TFA) were co-crystallised with 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP) producing organic salts of (pCA&minus;)(2A4MP+) (1), (pCA̶ )(2A6MP+) (2) and (TFA̶ )(2A4MP+)&middot;( 3 2 H2O) (3). For salt 3, water was included in the crystal structure fulfilling a bridging role. pCA formed a 1:1 salt with 2A4MP (Z&rsquo; = 1) and a 4:4 salt with 2A6MP (Z&rsquo; = 4). The thermal stability of the salts was determined using differential scanning calorimetry (DSC). Salt 2 had the highest thermal stability followed by salt 1 and salt 3. The salts were also characterised using Fourier transform infrared (FTIR) spectroscopy. Hirshfeld surface analysis was used to study the different intermolecular interactions in the three salts. Solvent-assisted grinding was also investigated in attempts to reproduce the salts

Solvates of selected fenamic acids with substituted pyridines: structure, thermal stability and desolvation

Mefenamic acid (MA) formed solvates with 2-picoline (2PIC), 3-picoline (3PIC), 4-picoline (4PIC) and 3-chloropyridine (3CLPYR). The solvates crystallized in the space group P1 with the carboxylic acid of MA hydrogen- bonded to the nitrogen of the substituted pyridine. Tolfenamic acid (TFA) formed solvates with 2PIC and 3PIC, the crystal structures successfully solved in the space groups P21/n and Pbca, respectively. The fenamate conformation varied depending on the acid and the included solvent. Similarities were observed in the structures involving MA. The two solvate structures of TFA had different packing arrangements. Grinding and slurry experiments were also successful for the preparation of all of the compounds except MA2PIC. Recrystallization, grinding and slurry investigations of MA and 2PIC yielded a polymorph; the structure was successfully solved in P21/n. Additionally, the thermal stability of the solvates was determined. Desolvation experiments were also performed and the resultant powders were analysed using powder X-ray diffraction.Cape Peninsula University of Technology and the National Research Foundation (South Africa

Salts of phenylacetic acid and 4-hydroxyphenylacetic acid with Cinchona alkaloids: Crystal structures, thermal analysis and FTIR spectroscopy

Seven salts were formed with phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (HPAA) and the Cinchona alkaloids; cinchonidine (CIND), quinidine (QUID) and quinine (QUIN). For all the structures the proton was transferred from the carboxylic acid of the PAA/HPAA to the quinuclidine nitrogen of the respective Cinchona alkaloid. For six of the salts, water was included in the crystal structures with one of these also incorporating an isopropanol solvent molecule. However HPAA co-crystallised with quinine to form an anhydrous salt, (HPAA−)(QUIN+). The thermal stability of the salts were determined and differential scanning calorimetry revealed that the (HPAA−)(QUIN+) salt had the highest thermal stability compared to the other salt hydrates. The salts were also characterized using Fourier transform infrared spectroscopy. (PAA−)(QUID+)·H2O and (PAA−)(QUIN+)·H2O are isostructural and Hirshfeld surface analysis was completed to compare the intermolecular interactions in these two structures.National Research Foundation (South Africa) and the Cape Peninsula University of Technology

Salts of Mefenamic Acid With Amines: Structure, Thermal Stability, Desolvation, and Solubility

ArticleSalt formation has been known to improve some physicochemical properties of active pharmaceutical ingredients particularly solubility. In this study, mefenamic acid (MA) formed salts with ethylenediamine (EDM), triethylamine (TA), 1-methylpiperazine (MP), and morpholine (MOP). In the salt structures studied, the proton of the carboxylic acid group of the MA molecule was transferred to a nitrogen atom of the amine. Both crystal structures of the ethylenediammonium and morpholinium salts were solved successfully by single-crystal X-ray diffraction in the space group PĪ. The triethylammonium and the 1-methylpiperazinium salts solved in Pbca and P21/c, respectively. The thermal behavior of the salts was investigated, and the desolvated powders were analyzed using powder X-ray diffraction. Grinding and slurry experiments were also investigated as alternate methods for preparation of the salts. The desolvation experiments yielded interesting results with the desolvation of (MA−)(MP+) resulting in MA form I, desolvation of (MA−)(TA+) gave mixtures of MA form I and MA form II, whereas desolvation of (MA−)(MOP+) gave MA form II. The solubility trend in water was determined as (MA−)(MP+) > (MA−)(TA+) > (MA−)(MOP+) > (MA−)(EDM+), with (MA−)(MP+) the most-soluble and (MA−)(EDM+) the least-soluble salt.The authors thank the Cape Peninsula University of Technology and the National Research Foundation (South Africa) for funding. The authors also thank Dr. Aurora J. Cruz Cabeza for useful discussions

Functional characteristics of Bambara groundnut starch-catechin complex formed using cyclodextrins as initiators

Bambara groundnut (BGN) starch extracted from BGN flour was modified through complexation methods using alpha and beta cyclodextrin. Complexation methods used included the microwave, co-evaporation and kneading methods. Cyclodextrin (alpha and beta) were used as initiators for grafting catechin to the BGN starch molecule. The functional properties of native and modified BGN starches were assessed. The swelling capacity of BGN starches increased with an increase in temperature. The swelling capacities of BGN starches ranged from 0.36 g/g (BGN starch modified through the co-evaporation method, beta cyclodextrin + catechin) to 4.84 g/g (BGN starch modified through the microwave method, beta cyclodextrin + catechin). Complexation methods significantly reduced the swelling capacity of native BGN starch. Temperatures had a significant (p ≤ 0.05) effect on the swelling capacity of BGN starches. The solubility of BGN starches ranged from 0.61 g/100 g (native BGN starch) to 46.04 g/100 g (BGN starch modified through the kneading method, alpha cyclodextrin); using water as a solvent. The water absorption of native and modified BGN starches ranged from 0.23 to 1.17 g/g, respectively. Starches complexed with β-cyclodextrin showed increased water absorption capacity in comparison to the starches complexed with alpha cyclodextrin. The modification methods had a significant (p ≤ 0.05) effect on the water absorption capacities of BGN starches. There was no significant difference in the oil absorption capacities of BGN starches and they ranged from 1.02 to 1.07 g/g. Pasting properties of BGN starches were assessed using a rapid visco analyser (RVA). The modified starches exhibited lower breakdown, setback, and final viscosities as well as significant increase in gelatinisation temperature compared to the native BGN starch