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To achieve efficient transdermal delivery of rutin, a microemulsion (ME) system was developed by incorporating deep eutectic solvents (DES) as the inner phase and surface-active ionic liquids (SAILs) as surfactants. The DES used in this study is choline chloride/polyethylene glycol (PEG) 200, while the SAILs used were 1-alkyl-3-methylimidazolium bromides (Cn mimBr) with alkyl chain lengths of 10, 12, and 16 (C10 mimBr, C12 mimBr, C16 mimBr). Structural characterization by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) showed that MEs incorporated with C10 and C12 mimBr formed a cylindrical structure, where C16 mimBr formed spherical structures. MEs containing C10 or C12 mimBr exhibited significantly higher skin permeability of rutin, approximately 6.8 times greater compared with conventional water-in-oil (W/O) MEs. These results suggested that SAIL-based MEs are one of the promising drug carriers in the transdermal delivery of rutin.

The asymmetric α-regioselective conjugate addition of 2-thienylacetones to nitrostyrenes was achieved using a tertiary amine-thiourea organocatalyst, affording the α-addition products in high yields with excellent stereoselectivities. This study provides the first demonstration of an asymmetric α-regioselective conjugate addition of 2-thienylacetones to nitroalkenes.

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.

The chemical analysis of Cladosporium tenuissimum yielded six 12-membered macrolides (1-6), including 2 new ones (1 and 2) and 4 other compounds (7-10). Comprehensive spectroscopic techniques were employed to establish the structures, whereas electronic circular dichroism (ECD) calculations and Mosher's analysis were performed to confirm the absolute configurations of new compounds. We evaluated the metabolites for their cytotoxic activities, antifungal activity, and α-glucosidase. Notably, compound 1 exhibited moderate antifungal activity against Alternaria solani and Botrytis cinerea with minimum inhibitory concentration (MIC) values of 25 μM, respectively. Compounds 4 and 5 had the best inhibition against A. solani and B. cinerea, better than the positive control, hymexazol. Remarkably, compound 6 inhibited α-glucosidase with IC₅₀ value of 160 μM, outperforming acarbose by 12-fold. Enzyme reaction kinetics and molecular docking were used to investigate potential α-glucosidase inhibition mechanisms. Moreover, compound 7 exhibited moderate cytotoxicity against HeLa cells (IC₅₀ = 15.27 ± 0.72 μM), more active than etoposide. Consequently, the results provide a solid foundation for developing bioactive metabolites of C. tenuissimum.

Cell-penetrating peptides (CPPs) have been widely applied as carriers in drug delivery systems (DDS) capable of transporting diverse biomolecules, including nucleic acids and highly hydrophilic low-molecular-weight compounds, into cells. Amphipathic CPPs composed of arginine and the α,α-disubstituted amino acid Aib (2-aminoisobutyric acid) have been investigated for their potential application as carrier peptides. In addition, the incorporation of d-amino acids into CPPs has been utilized as a strategy to confer resistance against proteolytic degradation, which is one of the major challenges associated with CPPs. In this study, we evaluated the structure, membrane permeability, and plasmid DNA (pDNA) delivery capability of (Arg-Arg-Aib)_n peptides with different combinations of l/d-Arg residues. Secondary structures were analyzed by circular dichroism (CD) spectroscopy, and their correlation with membrane permeability was examined. Consequently, α-helical peptides exhibited enhanced membrane permeability with increasing peptide chain length. In comparison between the same chain length of α-helical peptides and random-coil peptides, the difference in membrane permeabilities decreased as the peptide chain length increased. Notably, the peptide (l-Arg-d-Arg-Aib)₄ exhibited the highest protease resistance despite containing l-Arg residues and demonstrated pDNA transfection efficiency comparable to that of an α-helical peptide composed entirely of d-Arg residues. Optimization of l/d-Arg combinations for membrane permeability and gene delivery efficiency in (Arg-Arg-Aib)_n is useful for rationally designing amphipathic CPPs with l/d-amino acids.

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.

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.

Pseudocyclic arylbenziodoxaboroles are unique aryne precursors under neutral aqueous conditions that selectively react with tertiary organic phosphines or amines at room temperature to form the corresponding aryl-substituted quaternary phosphonium or ammonium salts in high yields. This reaction has been further extended to the preparation of tetraarylarsonium and tetraarylstibonium salts.

Acidic-environment targeting peptides (AEPs), which insert into cell membranes under acidic conditions, have been gaining attention as potential targeting ligands for acidic tissues such as tumors. Conventional AEPs have been taken from archaea or designed rationally; therefore, they have a risk of antigenicity. Here, we propose screening for AEPs from the human proteome. AEP candidates were screened from more than 20000 human proteome transmembrane peptides based on 4 conditions AEPs should fulfill. Twenty-seven peptides were found to satisfy the four conditions. The same number of candidate peptides were identified in the mouse membrane proteome, most of which originated from the orthologous membrane proteins identified in the human proteome. Four of the 27 peptides selected from the human proteome were synthesized with a fluorescence label attached or expressed as fusion proteins with green fluorescent protein to examine their acid-responsive accumulation in vitro and in vivo. We found that 1 of the 4 peptides performed similarly to the pH-low insertion peptide, the first reported AEP.

Bicyclo[1.1.0]butane (BCB) is a highly strained compound with unique reactivity. In this work, we discovered that a BCB derivative bearing an aryl and a diisopropylamide group undergoes an oxygen-mediated transformation to give the corresponding oxazolidin-4-one derivative in good yield under mild conditions (EtOAc, O₂, 40 °C). The structure of the product was confirmed by X-ray crystallographic analysis, and radical trapping experiments suggested that the reaction involves a radical pathway. This reaction enables direct conversion of BCB carbon atoms into a heterocyclic scaffold with a high atom economy.