Chemical & pharmaceutical bulletin最新文献

In screening for antibacterial agents from co-cultures of Mycobacterium smegmatis and microbial resources, such as actinomycetes and fungi, the known hydroxyquinone antibiotic griseorhodin A (1) was isolated from a co-culture of actinomycete strain TMPU-20A002 and M. smegmatis. Compound 1 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), with minimum inhibitory concentrations of 0.25 and 2.0 μg/mL, respectively. In silkworm infection models with MRSA and VRE, 1 exhibited therapeutic efficacy, with ED₅₀ values of 2.5 and 18 μg/larva·g, respectively. A pharmacokinetic analysis of silkworms revealed an elimination half-life of 4.4 h in the hemolymph, indicating a favorable metabolic profile. This is the first in vivo evaluation of griseorhodin A, including its pharmacological activity and metabolic behavior, and it highlights its potential as a candidate for the development of novel antibacterial agents.

The δ-opioid receptor (DOR) is a promising target for developing novel analgesics due to its lower risk of causing side effects compared to the μ-opioid receptor (MOR), which is commonly associated with dependence, respiratory depression, and other adverse effects. KNT-127, a DOR-selective agonist with a morphinan skeleton, offers analgesic and antidepressant benefits without inducing convulsions at therapeutic doses, unlike the conventional DOR agonist SNC80. While previous studies have suggested that KNT-127 exhibits reduced β-arrestin recruitment, a signaling pathway implicated in adverse opioid effects, the ligand structural basis for this biased signaling remains unclear. In this study, we explored the structure-signal relationships of KNT-127, focusing on its quinoline moiety, which is known to serve as an address domain responsible for DOR selectivity. Modifying the quinoline moiety by removing the aromatic rings reduced DOR selectivity and potency in relation to G-protein activation while diminishing both the potency and efficacy of β-arrestin recruitment. These results suggest that the morphinan skeleton is critical for reduced β-arrestin recruitment, while the quinoline moiety differentially modulates G-protein activation and β-arrestin recruitment. Together, our study expands the message-address concept, previously limited to receptor selectivity, by providing structural insights into the G-protein-biased agonism of DOR agonists, thereby guiding the design of safer DOR-targeting therapeutics.

The purpose of the present study was to predict the intra-individual variability (%CV_intra) values of C_max using observed parameters of physicochemical and pharmacokinetic for a variety of formulations. A database was used to summarize the parameters of clinical bioequivalence (BE) studies of oral drugs, including the highest dose tablets, orally disintegrating tablets (ODT), and capsules (278 formulations [238 compounds]). As explanatory variables, %CV_intra, inter-individual variability (%CV_inter), absolute bioavailability (BA), T_max, t_1/2, dose number (Do), and dissolution rate (D%) were selected. Explanatory variables correlated with %CV_intra were identified by multivariate analysis and grouped quantitatively by K-means clustering analysis. The %CV_intra predictions compared three models of multiple regression, boosting tree, and neural network. In the neural network, the coefficient of determination (R²) and the root mean square error (RMSE) were the best, with good correlation between the predicted and observed values of the test data (R² = 0.69). The explanatory variables used in this study are readily available from the literature of reference formulation and in vitro measurement. Therefore, predicting %CV_intra for C_max without conducting pilot studies is useful for clinical planning in the early stages of generic drug development. We believe that we could further contribute to speeding up and reducing the cost of generic drug development.

New nucleoside derivatives containing the imidazole (Imd), pyridine or pyrimidine catalytic group were designed for site-specific acetylation of 2'-OH of the RNA ribose moiety. When the RNA substrate was acetylated in the presence of acetic anhydride under alkaline conditions, Probe (Imd) containing the imidazole catalytic group acetylated with a high selectivity to the 2'-OH of the uridine opposite the catalytic nucleotide. Probe (Py-4N) containing the pyridine group showed a higher catalytic activity under neutral conditions with a high selectivity for the 2'-OH group of the 5' side of the uridine opposite the catalytic nucleotide in about 80% modification yield within 10 min. This study has shown that the oligodeoxynucleotide incorporating the new nucleotide derivative with the catalytic group can be a useful tool for site-selective acetylation of RNA 2'-OH.

Mini-tablets (MTs) allow for dosage adjustments according to children's weight and age. However, it is difficult to manufacture MTs with robust physical properties, and various formulation techniques are required. Adding cellulose nanofiber (CNF), a highly functional biomass material, to MTs improved the hardness and disintegration; however, the large variation in the weight and drug content of the resulting MTs remained a challenge. Therefore, this study analyzed the physical properties of CNF-containing MTs of different particle sizes and evaluated the effect of the particle size on MT manufacturing. CNF₃₀₀, with an average particle size of approximately 300 µm, was pulverized to prepare CNF₁₀₀, averaging 100 µm. The formulation included CNF (10, 30, and 50%), lactose hydrate, paracetamol, and magnesium stearate. The pharmaceutical powders mixed were loaded into a rotary tablet press equipped with a 3-mm multiple-tip tooling and compressed at 2, 5, and 8 kN forces. CNF₁₀₀-containing MTs were manufactured via direct powder compression, and they showed lower variations in weight and drug content than those containing CNF₃₀₀. The tensile strength of MTs containing CNF₁₀₀ was smaller than that of those containing CNF₃₀₀; however, a strength of ≥1 MPa (corresponding to ≥30 N hardness of a regular tablet) was obtained by setting the compression force to ≥5 kN. The MTs containing 30% CNF₁₀₀ disintegrated in ≤30 s, regardless of the compression force. Thus, using smaller CNF particle sizes enabled the manufacturing of an orally disintegrating MT with adequate hardness and disintegration properties while also minimizing variations in MT weight and drug content.

Lysosome-targeting chimera (LYTAC) efficiently degrades specific membrane proteins. In a previous study, we synthesized and reported human epidermal growth factor receptor 2 (HER2)-LYTAC (that induces the degradation of HER2 protein using DNA aptamers that binds to insulin-like growth factor receptor 2 and HER2). In this study, we designed and synthesized linker-length-modified HER2-LYTAC derivatives with varying distances between the DNA aptamers and assessed their protein degradation-inducing activity. The results revealed that HER2 degradation varied significantly with the linker length. Notably, HL5L-HER2-LYTAC with a 5-bp longer linker than that of the original HER2-LYTAC-exhibited equivalent or enhanced activity and significantly inhibited the proliferation of HER2-positive cancer cells. This is the first study to assess the effect of linker length in designing LYTAC molecules using bispecific DNA aptamers and offers valuable insights into the molecular design of nucleic acid-based LYTACs.

Guanine quadruplexes (G4s) are non-canonical nucleic acid structures that have emerged as attractive therapeutic targets owing to their involvement in diverse biological processes. Additionally, peptides derived from G4-binding proteins provide promising platforms for selective G4 recognition. In this study, we explored the G4-binding capacity of arginine-glycine-glycine (RGG)-rich sequences derived from the RGG3 domain translocated in liposarcoma/fused in sarcoma (TLS/FUS), a known G4 RNA binding protein. In this study, we synthesized a library of overlapping 15-mer peptides and evaluated their G4-binding affinities. Among the 10 evaluated native sequences, several peptides demonstrated measurable affinities toward G4 RNA structures, with STK5-1 exhibiting the highest G4-binding affinity. Furthermore, to investigate the impact of conformational constraints on G4 recognition, we introduced (E)-methylalkene dipeptide isosteres (MADIs) into selected Gly-Gly motifs, generating a series of RGG peptidomimetics. Subsequent binding assays revealed that some of these MADI peptidomimetics exhibited enhanced affinity and selectivity compared with their unmodified counterparts. Our findings offer new insights into the sequence and structural features governing G4-binding, establishing a foundation for the further development of peptide-based G4 ligands.

Many antimicrobial peptides (AMPs) exert their activity by disrupting the integrity of the bacterial plasma membrane. One of the membrane-disrupting mechanisms of AMPs involves the formation of toroidal pores, composed of α-helices and lipid headgroups. These pores enable the diffusion of lipid molecules to the opposite leaflet without exposing their headgroups to the hydrocarbon core. Consequently, an increase in lipid transbilayer diffusion (flip-flop) in the presence of AMPs is an important characteristic for AMP structure and function. However, real-time monitoring of the rapid flip-flop in the presence of transmembrane pores has not been achieved because of the permeation of membrane-impermeable reagents and/or the low time resolution of the conventional assays. Herein, we have developed a fluorescence quenching-based flip-flop assay. The flip-flop rates obtained by our method were consistent with those measured by the conventional dithionite reduction assay, confirming the reliability of our approach. The real-time monitoring of the flip-flop process in the presence of the AMP, magainin 2, using the self-quenching assay suggested that the disordered toroidal pores composed of 2 magainin molecules facilitate flip-flop. The newly developed assay will provide a better understanding of the interactions between AMPs and lipid bilayers.

In this study, waste basil seed (BS) was prepared and evaluated for the removal of methylene blue (MB) dye from aqueous media. BS was characterized using scanning electron microscopy, specific surface area, surface functional groups, and the point of zero charge (pH_pzc). Spherical particles were observed in virgin BS. The specific surface area and pH_pzc value were 0.265 m²/g and 5.59, respectively. In addition, acidic and basic surface functional groups were measured as 0.050 and 0.605 mmol/g, respectively. The MB adsorption study demonstrated that the adsorption capacity increased with increasing initial concentration (10-100 mg/L) and with decreasing temperature (45 -7°C). The pH of the MB solution significantly affected adsorption, with the highest uptake observed at the neutral and basic pH levels. The data fitted well to the Langmuir isotherm model and the pseudo-2nd-order model, with correlation coefficients of 0.899-0.993 and 0.996, respectively, under the tested conditions. Furthermore, elemental distribution analysis, binding energy evaluation, and adsorption capability revealed that MB adsorption on the BS surface was closely related to the cellulosic hydrocolloid components. Overall, BS exhibited a promising adsorption capacity and could serve as an effective material for MB removal from aqueous media.

Ultra performance liquid chromatography (UPLC)-high resolution (HR)MS/MS and feature-based molecular networking analysis were performed for the extract of a fungus, Arachnomyces bostrychodes, obtained from a cold seep chemosynthetic ecosystem, revealing the presence of new peptides. LC-MS-guided purification afforded three new cyclic tetrapeptides (3-5) containing two N-methyl-l-leucine residues. During the isolation procedure, a new benzophenone (1) and MDN-0093 (2) were isolated. Compounds 4 and 5 exhibited cytotoxicity against HeLa cells with IC₅₀ values of 3.1 and 5.8 μM, respectively.