Notes

Gamma-enolase: any well-known tumour gun, with a less-known position in most cancers.
This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound 2 showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites in vitro. In this article, we extended the structure-activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, the permeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl group with a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound 21 displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound 21 also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.We report on the development of an electroformation technique for the preparation of particulate (particle-based) emulsions. These oil-in-water (here, lipid phase acts as an "oil") emulsions were prepared using nonlamellar lipid phases. Such emulsion particles offer high hydrophobic volumes compared to conventional lipid particles based on lamellar phases (vesicles/liposomes). In addition, the tortuous internal nanostructure contributes through greater surface area per volume of lipid particles allowing an enhanced loading of payloads. The electroformation method makes use of a capacitor formed from two indium tin oxide coated conductive glass surfaces separated by a dielectric aqueous medium. This capacitor setup is enclosed in a custom-designed 3D-printed unit. Lipid molecules, deposited on conductive surfaces, self-assemble into a nanostructure in the presence of an aqueous medium, which when subjected to an alternating current electric field forms nano- and/or microparticles. Optical microscopy, dynamic light scattering, and small-angle X-ray scattering techniques were employed for micro- and nanostructural analyses of electroformed particles. With this method, it is possible to produce particulate emulsions at a very low (e.g., 0.0005 wt % or 0.5 mg/mL) lipid concentration. We demonstrate an applicability of the electroformation method for drug delivery by preparing lipid particles with curcumin, which is a highly important but water-insoluble medicinal compound. As the method employs gentle conditions, it is potentially noninvasive for the delivery of delicate biomolecules and certain drugs, which are prone to decomposition or denaturation due to the high thermomechanical energy input and/or nonaqueous solvents required for existing methods.Nonequilibrium processes, including physical aging, belong to the most challenging phenomena of glassy dynamics. One of the fundamental problems that needs clarification is the effect of material polarity on the time scale of the structural recovery of glass. The importance of this issue arises from practical applications and recent findings suggesting a substantial contribution of dipole-dipole interactions to the dielectric permittivity spectra of polar glass-formers. Herein, we use dielectric spectroscopy to investigate structural relaxation and aging dynamics of highly polar glass-former 4-[(4,4,5,5,5-pentafluoropentoxy)methyl]-1,3-dioxolan-2-one (FPC), a derivative of propylene carbonate with εs = 180 and μ = 5.1. We show that ε″(tage) data of FPC at Tage less then Tg reveal complex behavior resulting from considerable cross-correlation effects. Namely, two characteristic aging time scales, reflecting the evolution of cross-correlation mode and generic structural relaxation toward equilibrium, are obtained at a given Tage. Furthermore, a single stretched exponential behavior of ε″(tage) has been received for weakly polar carvedilol with negligible dipole-dipole interactions.Molecular adsorption to the nanoparticle surface may switch the colloidal interactions from repulsive to attractive and promote nanoparticle agglomeration. If the nanoparticles are magnetic, then their agglomerates exhibit a much stronger response to external magnetic fields than individual nanoparticles. Coupling between adsorption, agglomeration, and magnetism allows a synergy between the high specific area of nanoparticles (∼100 m2/g) and their easy guidance or separation by magnetic fields. This yet poorly explored concept is believed to overcome severe restrictions for several biomedical applications of magnetic nanoparticles related to their poor magnetic remote control. In this paper, we test this concept using curcumin (CUR) binding (adsorption) to β-cyclodextrin (βCD)-coated iron oxide nanoparticles (IONP). CUR adsorption is governed by host-guest hydrophobic interactions with βCD through the formation of 11 and, possibly, 21 βCDCUR inclusion complexes on the IONP surface. A 21 stoichiometry is supposed to promote IONP primary agglomeration, facilitating the formation of the secondary needle-like agglomerates under external magnetic fields and their magneto-microfluidic separation. The efficiency of these field-induced processes increases with CUR concentration and βCD surface density, while their relatively short timescale ( less then 5 min) is compatible with magnetic drug delivery application.Anti-Aβ therapy has dominated clinical trials for the prevention and treatment of Alzheimer's disease (AD). However, suppressing Aβ aggregation and disintegrating mature fibrils simultaneously remains a great challenge. In this work, we developed a new strategy using a charged tubular supramolecule (CTS) with pillar[5]arene as the backbone and modifying amino and carboxyl groups at the tubular terminals (noted as CTS-A, CTS-A/C, and CTS-C, respectively) to suppress Aβ fibrillation for the first time. According to the spectroscopic and microscopic characterizations, Aβ40 fibrillation can be efficiently suppressed by CTS-A in a very low inhibitorpeptide (IP) molar ratio (110). A greatly alleviated cytotoxic effect of Aβ peptides after the inhibition or disaggregation process is further disclosed. The well-organized supramolecular structure drives multivalent interaction and gains enhanced efficiency on amyloid fibrillar modulation. These results open a new path for the design of supramolecules in the application of AD treatment.The catalytic hydroarylation of nonactivated alkenes with aniline is a reaction of high interest, aiming at providing C-functionalized aniline derivatives that are important precursors for the fabrication of polyurethanes. However, this reaction remains a longstanding goal of catalysis, as it requires one to simultaneously address two important goals (1) the very low reactivity of nonactivated alkenes and (2) control of the hydroarylation/hydroamination selectivity. As a result, the hydroarylation of aniline is mostly restricted to activated alkenes (i.e., featuring ring strain, conjugation, or activation with electron-donating or -withdrawing groups). Here we show that the combination of bismuth triflate and hexafluoroisopropanol (HFIP) leads to the formation of highly active catalytic species capable of promoting the hydroarylation of various nonactivated alkenes, such as 1-octene, 1-heptene, and 1-undecene, among others, with aniline with high selectivity (71-92%). Through a combined experimental and computational investigation, we propose a reaction pathway where HFIP stabilizes the rate-determining transition state through a H-bond interaction with the triflate anion, thus assisting the acid catalyst in the hydroarylation of nonactivated alkenes. From a practical point of view, this work opens a catalytic access to C-functionalized aniline derivatives from two cheap and abundant feedstocks in a 100% atom-economical fashion.The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure-activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders von Hippel-Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Apoptosis inhibitor Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.With the increasing improvement of people's living standards, hyperglycemia has become one of the most frequent diseases in the world. The current drug therapy may have some negative effects and even cause some complications. As one of the most popular functional ingredients, probiotic bacteria have been proven to play important roles in balancing the glucose homeostasis level in animal and human clinic trials. In this perspective, we sorted three types of probiotics, discussed probiotic safety evaluation, and listed the known probiotic functional foods that assist to control glucose homeostasis. Then, the further summarization of the mechanisms on how probiotic bacteria could regulate glucose homeostasis and the developing trend of probiotic functional foods were discussed.Phosphorylated cellulose nanofiber (CNF) is attracting attention as a newly emerged CNF with high functionality. However, many structural aspects of phosphorylated CNF remain unclear. In this study, we investigated the chemical structures and distribution of ionic functional groups on the phosphorylated CNF surfaces via liquid-state nuclear magnetic resonance measurements of colloidal dispersion. In addition to the monophosphate group, polyphosphate groups and cross-linked phosphate groups were introduced in the phosphorylated CNFs. The proportion of polyphosphate groups increased as the phosphorylation time increased, reaching ∼30% of all phosphate groups. Only a small amount of cross-linked phosphate groups existed in the phosphorylated CNF after a prolonged reaction time. Furthermore, phosphorylation of cellulose using urea and phosphoric acid was found to be regioselective at the C2 and C6 positions. There existed no significant difference between the surface degrees of substitution at the C2 and C6 positions of the phosphorylated CNFs.Fibroblast growth factor receptor 1 (FGFR1) is an integral membrane protein that transmits prolife signals through the plasma membrane. Overexpression of FGFR1 has been reported in various tumor types, and therefore, this receptor constitutes an attractive molecular target for selective anticancer therapies. Here, we present a novel system for generation of intrinsically fluorescent, self-assembling, oligomeric cytotoxic conjugates with high affinity and efficient internalization targeting FGFR1. In our approach, we employed FGF1 as an FGFR1 recognizing molecule and genetically fused it to green fluorescent protein polygons (GFPp), a fluorescent oligomerization scaffold, resulting in a set of GFPp_FGF1 oligomers with largely improved receptor binding. To validate the applicability of using GFPp_FGF1 oligomers as cancer probes and drug carriers in targeted therapy of cancers with aberrant FGFR1, we selected a trimeric variant from generated GFPp_FGF1 oligomers and further engineered it by introducing FGF1-stabilizing mutations and by incorporating the cytotoxic drug monomethyl auristatin E (MMAE) in a site-specific manner.
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