Chemical & pharmaceutical bulletin最新文献

The structural integrity of inhalable liposomal carriers is a key determinant of drug release behavior, pulmonary residence time, and therapeutic efficacy. This study aimed to establish a compensated Förster resonance energy transfer (FRET)-based platform for the quantitative assessment of liposome integrity throughout the inhalation delivery process. By compensation for donor fluorescence bleed-through and direct acceptor excitation, the method enables accurate quantification of FRET signals from liposomes co-loaded with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate (DiD, donor)/1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, acceptor), using both spectrofluorometry and macroscopic imaging. Upon treatment with Triton X-100, decreases in the compensated FRET/donor ratio were detected at lower concentrations than those required to induce measurable changes in membrane anisotropy and within the same concentration range as the onset of encapsulated 6-carboxyfluorescein release. Using this platform, in vitro aerosol characterization with an Andersen cascade impactor enabled simultaneous analysis of aerodynamic particle size distribution and stage-specific liposome integrity. In vivo experiments in mice-including ex vivo lung imaging and bronchoalveolar lavage fluid analysis-revealed a time-dependent decline in liposome integrity during pulmonary residence. This ability to monitor carrier structural stability from initial deposition through residence-an aspect not readily achieved with conventional single-fluorophore labeling-offers significant advantages for formulation development, stabilization strategies, and dosing regimen optimization. The FRET-based platform could, in principle, be adapted for use with other standardized cascade impactors such as the Next Generation Impactor and is expected to be applicable to a wide range of lipid-based or polymeric nanocarriers, including inhalable vaccines and nucleic acid therapeutics.

In this study, two novel thiabendazole (TBZ) cocrystals were successfully prepared by the solvent evaporation method through the selection of structurally similar, highly water-soluble resorcinol (RES) and phloroglucinol (PHG) as cocrystal formers (CCFs), together with TBZ, which is inherently water-insoluble. The two TBZ cocrystals were comprehensively characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermogravimetric-differential scanning calorimetry (TG-DSC), and Fourier-transform IR spectroscopy (FT-IR). Hirshfeld surface analysis was employed to visually illustrate the types and distributions of intermolecular interactions in the two TBZ cocrystals. The solubility and dissolution of the two TBZ cocrystals were measured, respectively. Both cocrystals exhibited superior aqueous solubility compared with TBZ. Specifically, the thiabendazole-phloroglucinol (TBZ-PHG) cocrystal demonstrates that the increased density of hydroxyl groups in the coformer enhances the hydrogen bonding interactions, leading to the formation of a 2 : 1 (TBZ:PHG) stoichiometric cocrystal. The non-parallel arrangement of TBZ molecules in the cocrystal disrupts the close π-π stacking, thereby enhancing solvent penetration. Consequently, its aqueous solubility is improved to a greater extent.

2-Oxoglutarate-dependent non-heme iron oxygenases (2OGX) catalyze a broad spectrum of oxidative transformations, including hydroxylation, halogenation, desaturation, cyclization, rearrangement, and endoperoxidation, through a conserved HxD/E…H facial triad and Fe(IV)=O chemistry. Their functional diversity arises from structural elements that define the catalytic pocket. Substrate-binding architectures can be categorized into four recurrent motifs-the conserved lip (CLip), conserved lid (CLid), specific lid (SL), and dimer lid (DL)-together with the major β-sheet framework (βI-βVI); mutations in these lid/lip elements and within β-strands collectively govern substrate entry, positioning, and radical partitioning. This review discusses representative case studies organized by reaction class-hydroxylation/halogenation, cyclization/rearrangement, endoperoxidation, and free amino acid oxidation-to illustrate how targeted substitutions in these motifs enable rational reprogramming of reactivity. Examples include hydroxylases converted to halogenases, fungal enzymes redirected to construct alternative meroterpenoid scaffolds, endoperoxidases generating non-natural products, and amino acid hydroxylases engineered for halogenation, desaturation, or aziridination. These studies highlight the structural plasticity of 2OGX scaffolds and establish them as programmable biocatalysts, with advances in structural biology and computational design expected to accelerate their application in synthetic biology, natural product discovery, and drug development. The literature published from 2015 through September 2025 is reviewed.

The development of scalable synthesis of the C21-C34 segment, a key intermediate for aplyronine A and its analogs, is reported. Marshall propargylation and Noyori asymmetric hydrogen transfer served as key reactions for the stereoselective construction of the desired C21-C34 segment on a gram scale. Further transformation of the segment successfully afforded the side chain analog that exhibited actin depolymerization activity similar to that previously reported.

Herein, we report the catalytic asymmetric intramolecular dearomative coupling of tethered phenols in ortho-para fashion under aerobic conditions. Cooperative catalysis with a chromium-salen complex/nitroxyl radical enabled the desired transformation to proceed at ambient temperature under oxygen atmosphere. A range of tethered phenols were efficiently converted into spirocyclic 2,4-dienones in moderate to good yields and enantioselectivities (up to 68% enantiomeric excess (ee)).

Site-selective reactions are important tools in the synthesis of useful multisubstituted compounds, including pharmaceuticals and functional molecules. Such reactions convert functional groups in a selective manner, thereby enabling the synthesis of various compounds with different substitution patterns from a single starting compound. Although a number of transition metal-catalyzed site-selective reactions have been developed, site-selectivity is usually controlled by the substrate, limiting the scope of the reaction. In contrast, catalyst-controlled site-selective reactions of single substrates have been reported, wherein ligand-controlled reactions are of particular interest. Previously, our group developed hydroxyterphenylphosphine ligands to achieve the palladium-catalyzed ortho-selective cross-coupling reactions of dihalogenated phenols/anilines. In this system, the hydroxy groups of the ligand bind to the substrate via the metal, and the proximity of palladium to the halogen at the ortho-position accelerates the reaction at this less reactive position. These reactions have been employed to synthesize multisubstituted benzofurans and indoles from dichlorophenols/anilines using a one-pot ortho-selective Sonogashira coupling/cyclization/Suzuki-Miyaura coupling protocol. The developed catalyst also has enabled the direct C3-selective arylation of N-nonsubstituted indoles, and both tricyclic pyrroloindolines and pyridoindolines have been obtained from tryptamine derivatives via a C3-dearomative arylation/cyclization strategy. Furthermore, the site-selective arylation of N-nonsubstituted 1H-pyrroles has been achieved by changing the ligand, and the reaction proceeded selectively at the C2 or C3 position, yielding 2,2,5-trisubstituted 2H-pyrroles and other compounds whose preparation is challenging via conventional approaches. Finally, the regioselective synthesis of polycyclic aromatic compounds using appropriate palladium catalysts has been performed using the site-selective approach.

This study aimed to develop inhalable dry powder formulations of naked plasmid DNA (pDNA) for pulmonary gene delivery using an electrospinning (ES) technique. Nanofiber mats comprising polyvinyl alcohol (PVA), pDNA encoding firefly luciferase, and either D(-)-mannitol (Man) or lactose monohydrate (Lac) were fabricated and subsequently cryomilled into fine, respirable particles. Agarose gel electrophoresis revealed partial degradation of pDNA during both ES and milling processes, with Lac-based nanofiber mat and powder showing greater pDNA integrity than Man-based formulations. Intratracheal administration of the ES-derived powders in mice led to successful in vivo gene expression, with Man-based powders milled for 0.5 min yielding the highest luciferase activity. Pulmonary imaging using indocyanine green showed that dry powders exhibited extended lung residence compared to aqueous formulations, likely due to improved mucosal adhesion and slower dissolution. Remarkably, the ES-generated pDNA powders demonstrated superior transfection efficiency over both naked pDNA and pDNA-polyethyleneimine complexes, despite some loss in pDNA integrity. These findings highlight the importance of dispersibility and lung retention in achieving effective pulmonary gene transfer. The ES approach represents a promising platform for producing inhalable pDNA powders, offering a non-invasive gene therapy option for respiratory diseases.

Through the heterologous expression of a highly reducing polyketide synthase and a thioesterase from the apeml cluster, a putative macrolide biosynthetic gene cluster on the genome of Aspergillus petrakii, we obtained a naturally new 10-membered macrolide (1) and recifeiolide (2), a known 12-membered macrolide. To obtain modified macrolides, feeding experiments using Aspergillus oryzae transformants expressing individual modification enzymes were employed, resulting in the isolation of aspinolide A (3) and 2 new macrolides, petrakilides A (4) and B (5). These findings highlight a promiscuous enzymatic cascade capable of generating macrolides with distinct scaffolds and different ring sizes.

Twelve side-chain fluorinated 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D₃ (AH-1) analogs were designed, synthesized, and evaluated regarding their biological activities. Synthesis was carried out employing the palladium-catalyzed Trost coupling reaction between side-chain fluorinated CD-ring bromo-olefins 41-52 and A-ring enyne 53. Some analogs, including C26,27-hexafluoro-AH-1 (31) and 24,24-difluoro-AH-1 (34), exhibited much higher human vitamin D receptor binding affinity, VDR-ligand binding domain transcriptional activity, osteocalcin promoter transactivation activity, and metabolic resistance to CYP24A1-mediated inactivation than 1α,25(OH)₂D₃.