Chemical & pharmaceutical bulletin最新文献

The Hippo signaling pathway plays a central role in regulating cell growth, and dysregulation of its downstream effector Yes-associated protein (YAP) leads to tumorigenesis. Verteporfin (VP), a clinically approved drug, inhibits YAP-TEA domain (TEAD) complex formation, yet its binding mechanism remains unclear. In this study, we conducted a comprehensive in silico analysis of all 4 VP isomers within the context of the full-length YAP-TEAD complex. The complex structure was modeled using AlphaFold2 multimer, which provided sufficient accuracy for docking simulations despite incomplete experimental data on YAP. Docking calculations were performed against 2 grids, one centered on a predicted druggable pocket and the other on the YAP-TEAD interface. A total of 304 poses were generated, and the top-scoring 100 were clustered using protein-ligand interaction fingerprints. Clusters derived from the interface grid revealed strong interactions with residues critical for YAP-TEAD binding. Among the 4 isomers, Ia-2 consistently showed the most favorable binding free energies. Notably, Cluster 7 highlighted a unique Ia-2 binding mode involving simultaneous interactions with Met86 and Arg87, suggesting a competitive mechanism at the YAP-TEAD interface. These results suggest that structural chirality may influence binding stability and interaction patterns, and that the Ia-2 isomer is predicted to preferentially stabilize an inhibitory binding mode. This study provides the first systematic comparison of all VP isomers with full-length YAP and suggests that isolating Ia-2 from Visudyne may enhance anticancer efficacy. The findings further support the rational strategies for designing selective YAP-TEAD inhibitors.

A new depsidone, termed mollicellin Z2 (1), and three known mollicellins D, H, and I (2-4), were isolated from cultured Chaetomium brasiliense NBRC 6548 mycelia. The structure of 1 was determined from one dimensional (1D) and 2D-NMR and high resolution electron ionization (HREI)MS spectra. It is the first 4-desmethyl mollicellin analogue found to contain a C-7 prenyl group and is likely generated via a biosynthetic pathway that is distinct from those that produce the 27 known analogues. This is the first report of mollicellin derivatives with antibacterial activity against nontuberculous mycobacteria.

Mucociliary clearance is a unique defense mechanism that forcibly transfers micron-sized substances deposited on the airway epithelium from the lungs, but may interfere with inhalation therapy. The application of mucoadhesive agents to inhaled formulations is expected to improve their efficacy by prolonging the drug residence time in the lungs through inhibited mucociliary clearance. In the present study, we attempted to develop new inhaled spray-freeze-dried (SFD) powders with high deagglomeration and pulmonary retention abilities by combining hydroxypropyl cellulose (HPC) of different molecular weights as a mucoadhesive agent and dileucine (diLeu) as a dispersion enhancer. The incorporation of diLeu into SFD powders resulted in a rough surface structure with large cavities and improved their deagglomeration abilities. In addition, the incorporation of HPC of lower molecular weights resulted in SFD powders with higher deagglomeration abilities. On the other hand, SFD powders with HPC and diLeu showed similar particle size distributions to that with trehalose (Tre) and diLeu after emission from a device regardless of the molecular weight of HPC incorporated. A biodistribution study through intratracheal administration to mice revealed that pulmonary drug retention was longer with SFD powders with HPC and diLeu than with a drug solution or SFD powder with Tre and diLeu, and also that HPC of a high molecular weight (approx.100000) provided the highest pulmonary retention ability of the SFD powder. These results strongly indicate that the molecular weight of HPC incorporated is a critical factor that markedly affects both the deagglomeration and pulmonary retention abilities of SFD powders.

A concise approach is presented for preparing 4'-modified thymidines from oxime imidates using readily generated 4'-carbon radicals. This method produces 4'-modified thymidines from natural thymidine using the Mitsunobu reaction, the protection of 3'-hydroxy group (when necessary), and 1,5-hydrogen atom transfer (1,5-HAT)/intermolecular 1,4-addition with electron-deficient olefins. Moreover, using a one-pot synthesis involving 1,5-HAT/intermolecular 1,4-addition, followed by the hydrolysis of the imidate intermediate under basic conditions, 4'-modified thymidine was diastereoselectively isolated. This is because the 4'-isomer transferred to the water layer in the work-up process.

To search for safe and efficient anti-hypoxia active molecules, 27 derivatives were synthesized by introducing aminoalkyl groups at daidzein's position-7 and position-8. The structures of these derivatives were confirmed by ¹H-NMR, ¹³C-NMR, and mass spectrometry. The anti-hypoxia activity was evaluated in vitro using a cell hypoxia model established with the AnaeroPack-anaero. The results showed that 9 compounds significantly enhanced cell viability under hypoxic conditions, with compounds 2a, 2b, 4d, 5a, and 5d exhibiting in vitro anti-hypoxia activity significantly superior to daidzein. And the drug-like properties prediction results of the target compounds indicated that compounds 2a, 2b, 4d, 5a, and 5d may also demonstrate favorable pharmacokinetic properties. Further, the anti-hypoxia activity in vivo of these 5 derivatives were evaluated via normobaric hypoxia and hypobaric hypoxia models. The results indicated that all of the 5 compounds extended the survival time of mice under normobaric hypoxia to varying degrees, and they also alleviated oxidative stress damage to the brain and heart of mice under hypobaric hypoxia. Among these, compound 2a demonstrated superior anti-hypoxia activity both in vitro and in vivo compared to daidzein, making it worthy of further study as a potential candidate for an anti-hypoxia drug.

3-Acetyl-11-keto-β-boswellic acid is a pentacyclic triterpenoid. It is found in frankincense, which is the resin found in plants from the Boswellia genus. Single crystals of 3-acetyl-11-keto-β-boswellic acid methanol and acetonitrile solvates were obtained from the Boswellia serrata extract. X-Ray crystal structure analysis revealed the coexistence of a brominated derivative, 3-acetyl-11-keto-12-bromo-β-boswellic acid. Mass spectroscopy analysis confirmed the presence of the brominated derivative in the extract. These results provide a structural basis for insights into the chemical reactivity and possibly the biosynthesis of 3-acetyl-11-keto-β-boswellic acid and its related substances in B. serrata.

Density functional theory calculations on the cyclization of di-t-butyl 2-(2-aminophenyl)-2-methyl malonate (1) to t-butyl 3-methyloxindole-3-carboxylate (2) reveal that acetic acid-assisted protonation of the carbonyl oxygen atom reduces the activation Gibbs free energy significantly lower than methanol-assisted pathways. Experimental data confirm that reaction concentration plays a pivotal role in oxindole formation. Experimental results also indicate distinct reaction mechanisms at low and high concentrations. Achieving high enantioselectivity for chiral compound 2 in high-concentration reactions requires discovering a novel chiral acid.

Alkaline hydrolysis of the crude resin glycoside fraction from the leaves and stems of Ipomoea lacunosa L. (Convolvulaceae) yielded organic acid and glycosidic acid fractions. The organic acid fraction included n-decanoic and n-dodecanoic acids. Acidic hydrolysis of the glycosidic acid fraction yielded 3 monosaccharides (d-glucose, d-fucose, and l-rhamnose) and 2 known hydroxyl fatty acids (11S-hydroxytetradecanoic and 11S-hydroxyhexadecanoic acids). Treatment of the glycosidic acid fraction with trimethylsilyldiazomethane (in hexane) afforded 1 new glycosidic acid methyl ester (lacunosinic acid J methyl ester) and 6 known glycosidic acid methyl esters. Eight new resin glycosides (lacunosins V-XII) were isolated from the leaves and stems, along with 2 known resin glycosides. Their structures were determined using spectroscopic and chemical analyses. Three types of resin glycosides were identified: those with 18-membered macrolactone, those with 19-membered macrolactone, and those with non-macrolactone structures. All these compounds contained n-decanoic and n-dodecanoic acids as the organic acid components. Nine of the isolated resin glycosides were tested for cytotoxic activity against HL-60 human promyelocytic leukemia cells. One compound exhibited activity with an IC₅₀ value of 44.5 μM, while 3 compounds demonstrated moderate activity, with inhibition rates ranging from 53.5 to 68.7% at a concentration of 200 μM. In contrast, the remaining 5 compounds showed negligible effects even at 200 μM.