A direct dehydroxylative allylation reaction of benzylic alcohols with allylsilanes catalyzed by Brønsted acids in 1,1,1,3,3,3-hexafluoro-2-propanol was developed. A wide variety of secondary and tertiary benzylic alcohols are applicable to the reaction with various allyltrimethylsilanes, to provide the corresponding coupling products in high yields. Using this catalytic transformation, a concise and short-step synthesis of (±)-crucudiol was achieved.

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.

Artemisinin derivatives (ARTs) induce ferrous iron-dependent cell death (ferroptosis) by generating free radicals. Polymer-ARTs conjugates would be advantageous for cancer therapy. In this paper, we designed and synthesized the three types of ART-conjugated novel methacrylamide derivatives with or without a spacer between the aromatic group and the methacrylamide moiety for mechanochemical solid-state polymerization. The polymer conversion rate of ART-ethyl-MA and ART-methyl-MA for 90 min polymerization was achieved at 78 and 49%, respectively. However, ART-MA, which does not have a spacer, could not polymerize owing to the lowest unoccupied molecular orbital (LUMO) expanding from the methacrylamide moiety to the aromatic sites. The resulting poly(ART-ethyl-MA) produced the thermodynamically stable end-chain radicals through the main-chain scission via mechanical energy, and the generated mechanoradicals would play a role as an initiator of the surrounding monomers. The biocompatible sulfobetaine polymer-ARTs conjugates were fabricated through the mechanochemical solid-state copolymerization of sulfobetaine methacrylate (SBMA) and ART-ethyl-MA. The number average molecular weight and heterogeneity of the resulting water-soluble PSBMA-ARTs conjugates were 8000 g mol^–1 and 1.10, respectively. These results suggest that the design of solid monomers suitable for mechanochemical solid-state polymerization would require a molecular structure susceptible to single solid-state electron transfer (SSET) and the stability of mechanoradicals generated by the main-chain scission of resulting polymer. The mechanochemical solid-state copolymerization of zwitterionic monomer and hydrophobic monomer would be advantageous for the development of biocompatible polymer–drug conjugates.

Highly strained small-ring heterocycles have recently attracted considerable attention as three-dimensional alternatives to planar aromatic motifs in medicinal chemistry. Among these, 1-azabicyclo[1.1.0]butanes (ABBs) represent an exceptionally compact nitrogen-containing scaffold with potential utility as precursors to heterocyclic bioisosteres. Nevertheless, general and modular synthetic approaches to ABBs remain scarce. Herein, we report a concise three-step route to C3-substituted ABBs from readily accessible azetidinones. Central to this strategy is an intramolecular 3-exo-tet cyclization triggered by deprotonation with organolithium reagents, proceeding efficiently at low temperature. The method accommodates a broad range of aryl substituents with diverse electronic properties. In addition, vinyl chloride-containing substrates undergo tandem cyclization and elimination, enabling direct access to previously unreported alkynyl-substituted ABBs. Although ABB formation is highly efficient, the resulting compounds exhibit limited stability, leading to rapid decomposition during purification. To clarify the factors governing this behavior, density functional theory (DFT) calculations were performed. Comparison of strain and protonation energies across a series of ABB derivatives revealed that differences in intrinsic ring strain are minimal and cannot account for the observed instability. Instead, protonation energy calculations suggest that protonation promotes heterolytic cleavage of the central C–N bond, generating a benzylic cation whose stability is strongly influenced by substituent electronics. A pronounced linear correlation between calculated protonation energies and Hammett σ parameters supports a dominant role of resonance stabilization.

The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a representative click reaction with practical applications in various fields, including medicinal chemistry. Its product, 1,4-disubstituted triazoles, has an elongated, rod-like shape. The continued proliferation of 1,4-disubstituted triazole-based drug candidates is concerning because existing bioactive compounds are heavily biased toward rod-like shapes with limited structural diversity, even though three-dimensional compounds generally possess more favorable druglike properties. Replacing this triazole ring with a 1,5-disubstituted counterpart is expected to bend the molecular shape and address these limitations. Here, to evaluate this possibility, we constructed a new library in which the triazole rings of our previously established 7-azanorbornane-based 1,4-disubstituted triazole library were replaced with 1,5-disubstituted counterparts. We then assessed the effects of this change on molecular shape, aqueous solubility, and membrane permeability. Ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC), the most common synthetic method for 1,5-disubstituted triazoles, failed to produce the designed compounds, likely due to steric hindrance around the bicyclic scaffold. We therefore employed the reaction between acetylides and azides, which is relatively tolerant to steric hindrance, and successfully obtained the target 1,5-disubstituted triazoles, although not all designed compounds were produced. The 1,5-disubstituted triazoles synthesized here exhibited more three-dimensional shapes, greater structural diversity, and improved aqueous solubility than their 1,4-disubstituted counterparts, although no clear difference was observed in membrane permeability. These results suggest that replacing the triazole rings in CuAAC-derived libraries with 1,5-disubstituted counterparts is a promising strategy to construct libraries that exhibit greater three-dimensional structural diversity, and are more soluble in aqueous media.

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.

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.

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.

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.

Biologics represent a major advance in therapy, offering highly specific and potent treatment options for diseases previously difficult to manage; however, their administration routes are commonly limited to injection due to poor oral bioavailability, which can lead to patient inconvenience and adherence challenges. The pulmonary route offers a promising alternative, leveraging the lung’s large absorptive surface area, thin alveolar-capillary barrier, rich vascularization, and avoidance of first-pass metabolism to enable both local and systemic delivery. Effective inhaled biologic therapies require harmonizing the drug’s physicochemical properties with aerosol aerodynamic behavior and dissolution. The pharmacokinetic fate of inhaled biologics is further influenced by lung physiology, including airflow dynamics, airway structure, mucociliary clearance, and respiratory lining fluid composition. These factors present significant barriers to the stability, absorption, and retention of inhaled biologics. Extensive research efforts focus on optimizing formulations, inhalation devices, and excipients, alongside deepening the understanding of the biopharmaceutical characteristics of inhaled biologics. This review summarizes recent advances in inhalation systems of therapeutic peptides and proteins for systemic and local effects, emphasizing practical strategies to overcome key biopharmaceutical and physicochemical challenges, thus advancing the clinical potential of next-generation inhaled biologics.

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.

Dendrobium Sw. is one of the largest genera in the Orchidaceae. Most species belong to one of two major clades (the Asian and the Australasian clades) based on morphology and phylogenetic analyses using DNA sequences. Several Dendrobium species in the Asian clade are used in traditional herbal medicine, and many compounds have been isolated from them (e.g., phenanthrene derivatives, bibenzyl derivatives, and polysaccharides). Conversely, there are only a few reports on the compounds contained in the Australasian clade species. Due to its size and diversity, the Australasian clade could be expected to contain compounds of potential medicinal value as well. Previously, we constructed the HPLC profile of 18 Dendrobium species and identified the phenanthrene derivative 1,5-dimethoxyphenanthrene-2,7-diol (1) as a characteristic compound in certain species of the Australasian clade. In this study, we performed metabolic analyses based on ¹H-NMR to identify lineage-correlated metabolites for the Australasian clade. NMR profiling analysis also showed that 1 is a characteristic compound of the Australasian clade species. Additionally, pinoresinol (2) was predominantly detected in the Australasian clade. While syringaresinol (3) was widely detected in species from both clades, specimens from the Australasian clade tended to have higher concentrations. The simple ¹H-NMR profiling method enables rapid comparison of metabolites across multiple species, providing new insights into metabolic differences associated with evolutionary lineages that were not detectable by the previous HPLC profiling.

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.

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)).

We report here a synthesis of gem-difluorocyclopropanes via a copper-catalyzed C(sp³)–H addition of dioxolane to difluorocyclopropenes. The combinational use of silane and dibenzoyl peroxide was crucial for promoting the reaction, enabling access to gem-difluorocyclopropanes with an acetal moiety in a cis configuration.

We designed and synthesized an oligonucleotide acetylating reagent (Ac-probe) that selectively acetylates the 2′-OH groups of RNA upon forming a duplex with the target RNA. The Ac-probe can be readily prepared via a post-synthetic modification method using an oligodeoxynucleotide probe containing 4-thio-dT. During the acetylation reaction, 4-thio-dT is regenerated as the reaction proceeds. Notably, an efficient modification was observed when the complementary base of RNA to 4-thio-dT was cytosine or uracil, indicating the selectivity for the pyrimidine base.

Site-selective conjugation on aryl azides is hampered by a fundamental trade-off: electron-withdrawing groups that promote the reaction often preclude further functionalization, while versatile electron-donating groups suppress reactivity. We report a strategy that resolves this by using an ortho-amido group to activate an electron-rich aryl azide via an intramolecular hydrogen bond. This non-covalent interaction renders the ortho-amidoaryl azide significantly more reactive than its para-isomer and even activated alkyl azides, although competition experiments revealed that steric hindrance presents a counteracting effect. The principle was successfully applied to achieve excellent site-selectivity in a diazide molecule, favoring reaction at the aryl position. Its utility was further demonstrated in a highly selective classical Staudinger–Bertozzi ligation. This work establishes the ortho-amido group as a powerful controlling element, offering a new click conjugation platform that enables ready functionalization.

Immunoglobulin G (IgG)-binding peptides have been widely used in medicinal chemistry, particularly in the preparation of homogeneous antibody–drug conjugates (ADCs). The dissociation constant (K_d) and kinetic parameters (k_on and k_off) are critical determinants of peptide performance in such applications. In this study, we conducted a structure–activity relationship (SAR) analysis of the IgG-binding peptide 15-IgBP, focusing on Asp3, Tyr6, and Thr15, to identify more potent derivatives with favorable binding affinities and kinetic profiles. Peptides with appropriately tuned ionic structures exhibited rapid binding and release properties, whereas hydrophobic substitutions in solvent-exposed regions led to slower dissociation. By integrating these SAR findings, we identified the optimized affinity peptides, IAPG-2 and IAPG-3, with sub-nanomolar binding affinities (K_d = 0.753 and 0.705 nM, respectively).

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.

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.