Cyclic Methacrylate Tetrahydropyrimidinones: Synthesis, Properties, (Co)Polymerization

During radical polymerization of novel biocidal methacrylate guanidine monomers, a cyclic byproduct was discovered and identified as 2-imino-5-methyltetrahydropyrimidin-4(1H)-one (THP). Its methacrylate salt (MTHP) was synthesized and characterized via 1H and 13C NMR and pyrolysis chromatography. Synthesis conditions of both THP and MTHP were optimized to high yields, and both MTHP homopolymerization (in aqua) and copolymerization with diallyldimethylammonium chloride (in aqua in salt form) were successfully carried out with middle to high yields, providing a promising platform for potential tailored biocide polymers.

Study of the supramolecularly ordered layered structure of chitosan gel films

Structural and morphological features of chitosan gel films with a radially periodic structure, obtained by neutralizing the salt form of the polymer with sodium hydroxide or triethanolamine, were visualized by scanning electron microscopy. The formation of such supramolecularly ordered layered structures was found to obey diffusion kinetics and the regularities of Liesegang periodic precipitation. The revealed dependence of the morphostructure of our chitosan gel films on the neutralizing reagent used is due to differences in the diffusion rate of inorganic and organic substance, as well as some spatio-temporal features of the mass transfer process.

Crystal structures and Hirshfeld analysis of 4,6-dibromoindolenine and its quaternized salt

4,6-Dibromo-2,3,3-trimethyl-3H-indole, C11H11Br2N, exists as a neutral molecule in the asymmetric unit. The asymmetric unit of 4,6-dibromo-2,3,3-trimethyl-3H-indol-1-ium iodide, C12H14Br2N+·I−, contains one organic cation and one iodine anion. The positive charge is localized on the quaternized nitrogen atom. In the crystal, molecules of 4,6-dibromoindolenine are linked by C—Br...π halogen bonds, forming zigzag chains propagating in the [001] direction. The molecules of the salt form layers parallel to the (010) plane where they are linked by C—H...Br hydrogen bonds, C—Br...Br and C—Br...I halogen bonds. The Hirshfeld surface analysis and two dimensional fingerprint plots were used to analyse the intermolecular contacts present in both crystals.

Study on the Behavior of Electrochemical Extraction of Cobalt from Spent Lithium Cobalt Oxide Cathode Materials

The molten salt electrochemical method was used to reduce the Co in spent LiCoO2. The reduction mechanism of Co (III) in LiCoO2 was analyzed by cyclic voltammetry, square wave voltammetry, and open circuit potential. The reduction process of Co (III) on Fe electrode was studied in NaCl-CaCl2-LiCoO2 molten salt system at 750 °C. The results show that the reduction process of Co (III) is a two-step reduction: Co (III) → Co (II) → Co (0) and they are all quasi-reversible processes controlled by diffusion. Phase analysis (XRD) shows that Li+ and Cl2− in the molten salt form LiCl electrolysis experiments with different voltages were carried out, which proved the stepwise reduction of Co in LiCoO2.

GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors

Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; αMβ2), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study (NCT04060342) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.

Mechanistic PBPK Modelling to Predict the Advantage of the Salt Form of a Drug When Dosed with Acid Reducing Agents

Acid reducing agents (ARAs) reduce the dissolution rate of weakly basic drugs in the stomach potentially leading to lower bioavailability. Formulating the API as a rapidly dissolving salt is one strategy employed to reduce the impact of ARAs on dissolution of such drugs. In the present work, a model drug was selected with an immediate release formulation of the free base dosed in both the absence and presence of the ARA famotidine. In the latter case, bioavailability is restricted and several salt formulations were investigated. To simulate these drug products a mechanistic physiologically based pharmacokinetic (PBPK) model was built using the Simcyp Simulator, which illustrates the advantage of formulating an API as a salt compared to the free base form. The simulations use a mechanistic salt model utilising knowledge of the solubility product which was applied to predict the salt advantage. The developed PBPK model exemplifies that it can be critical to account for the surface pH and solubility when modelling the dissolution of low pKa bases and their salts in the gastric environment. In particular, the mechanistic salt model can be used to aid in screening and salt form selection where the aim is to mitigate effects of ARAs.

Electrochemically Obtained Polysulfonates Doped Poly(3,4-ethylenedioxythiophene) Films—Effects of the Dopant’s Chain Flexibility and Molecular Weight Studied by Electrochemical, Microgravimetric and XPS Methods

Electrochemically synthesized poly(3,4,-ethylenedioxythiophene) (PEDOT) films obtained in the presence of eight different polysulfonate dopants are comparatively studied by means of electrochemical quartz crystal microbalance (EQCM) and X-ray Photoelectron Spectroscopy (XPS). Differences with respect to oxidation and doping levels (OL and DL), polymerization efficiency and redox behavior are revealed based on the interplay of three factors: the type of the dopant (acid or salt form), flexibility of the polysulfonate chains and molecular weight of the polysulfonate species. For the rigid- and semi-rigid-chain dopants, use of the salt form results in higher OL and DL values and substantial involvement of solvent molecules in the course of polymerization and redox transitions whereas in the presence of their acid form compact PEDOT films with minor ionic-solvent fluxes upon redox transitions are formed. In contrast, use of the salt form of the flexible chain polysulfonates results in PEDOT with lower OL and DL in comparison to the corresponding acid form. Significant effects are observed when comparing flexible chain dopants with different molecular weights. From a practical point of view the present investigations demonstrate the large scope of possibilities to influence some basic properties of PEDOT (Ol and DL, intensity and type of the ionic and solvent fluxes upon redox transition) depending on the used polysulfonate dopants.

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.

Production of Natural Dye from Beet Roots (BETA VULGARIS L.) by using different Mordants

Dyes can be derived from nature by different part of plants. Natural dyes give the color like cool, warm colors that are with unique combinations. Dyes are made from natural resources like plants, animals, and minerals tend to produce colors that wash out easily. With most natural dyes, a mordant can be used to make color more permanent. In the mordanting process the fiber of wool, cotton is treated with a solution of a metal salt (usually an aluminum, chromium, copper, iron, or tin salt). Then the fiber is dyed with natural colors. Metals ions which are present in the salt form strong bonds with the fiber and also with the dye, therefore holding the dye to the fiber. In this activity, we can easily extract colored compounds from plant materials; use them to dye white cloths. A small difference in the dyeing technique or the use of different mordants with the same dye can shift the colors of a wide range or create new colors, which are not easily possible with synthetic dyes. Natural dyes are usually moth proof and can replace synthetic dyes in kid garments and food stuff for safety which have allergy to synthetic dyes.

Determination of the L-DOPA (L-3, 4-Dihydroxyphenylalanine) Content in Faba Bean (Vicia faba L.) Flowers and Faba Bean Flower Tea

This study aimed to determine the L-DOPA content in the flowers of some different faba bean genotypes and determine the L-DOPA levels in tea prepared from flowers. The experiment was carried out under the ecological conditions in Samsun by the Black Sea with 15 genotypes using a randomized complete block design in three replications. The flowers were harvested three times and the number of flowers and flower yields were determined. The L-DOPA content of the flower and flower tea were determined using HPLC. Different solvents were used to extract the L-DOPA from the faba bean flowers. As a result of the HPLC analyses, the highest L-DOPA yield was determined to be in the tea samples brewed with hot water. It was found statistical differences between genotypes in the second and third harvests for the number of flowers in the plant and the total number of flowers. Dry flower yields ranged from 11.33 to 37.78 kg da−1 while L-DOPA levels were 6.2 to 9.17 g 100g−1 in dry flowers and 6.69 to 9.23 g 100g−1 in infused tea. The study concluded that flower tea of faba bean can be investigate for medicinal purposes and that L-DOPA in the plant can be extracted by brewing without requiring any solvent. This shows that L-DOPA is in a salt form within the plant.