Chemical & pharmaceutical bulletin最新文献

N-Glycosylated RNA (glycoRNA) has been identified on the cell surface, and 3-(3-amino-3-carboxypropyl)uridine has been reported as a conjugation site of N-glycans on RNA. Although the association of glycoRNAs with various diseases has been reported, their biosynthetic mechanisms and biological roles remain unexplored. Here, we report the preparation of two species of N-glycan-conjugated 3-(3-amino-3-carboxypropyl)uridine as the minimal units of glycoRNA. Our synthesized glycoRNA unit would contribute to future biochemical research on glycoRNAs.

Veratridine is a neurotoxic compound classified into the cevanine group of the Veratrum alkaloids and is characterized by its highly functionalized hexacyclic structure. Here, we report the synthesis of the ABC-ring system of veratridine from a known cis-decalin. The cis-decalin was synthesized from 1,5-pentanediol by modification of a literature method. A site-selective acylation of the C3-hydroxy group with 3,4-dimethoxybenzoyl chloride, a chemo- and stereoselective (allyl)₂Zn-mediated C9-allylation, and ring closing metathesis were employed as key transformations to construct the ABC-ring system of veratridine.

Several approaches for synthesizing [1-¹³C]2-oxoglutaric acid were attempted, and the synthesis was successfully achieved in 4 steps from trimethylsilyl ¹³C-cyanide. The ¹³C-breath tests on rats were conducted by orally administering the newly synthesized [1-¹³C]2-oxoglutaric acid, the previously prepared [1'-¹³C]citric acid, and [1-¹³C]acetic acid as a control drug, and the results were compared. The results indicate that [1-¹³C]2-oxoglutaric acid and [1'-¹³C]citric acid may serve as potential substrates for assessing the TCA cycle flux.

Lipids, including fatty acids and phospholipids, play crucial roles in biological systems and are widely utilized in pharmaceutical and biomedical applications. However, their inherent hydrophobicity poses significant challenges for formulation and administration. In this study, we aimed to enhance the aqueous solubility of lipidic compounds by leveraging light-responsive molecular design. We synthesized azo-lipids by incorporating azobenzene units into a fatty acid and phosphatidylcholine, hypothesizing that light-induced trans-cis isomerization would improve solubility. The synthesized compounds exhibited reversible photoisomerization upon alternating UV (365 nm) and visible light irradiation, as confirmed by UV-vis spectroscopy and reverse-phase HPLC. The solubilization of these azo-lipids was quantified under UV-unirradiated and irradiated conditions. Azobenzene-incorporated phosphatidylcholine 2 exhibited a drastic increase in solubilization from 2.030 to 1008 µM (496-fold) after UV irradiation. This significant improvement was attributed to efficient photoisomerization and molecular bending in the cis, cis conformation, reducing intermolecular interactions. Our findings suggest that this on-demand aqueous solubilization strategy offers a novel approach for improving the handling, storage, and potential therapeutic administration of lipid-based compounds.

Despite the great strides in biopharmaceuticals and monoclonal antibodies today, natural products remain highly attractive as drug candidates. Therefore, building a library of natural products through total synthesis is critically important for drug discovery. This perspective article details the collective total synthesis of polycyclic natural products using "bioinspired reactions" that mimic natural product biosynthesis. It discusses the total syntheses of 20 natural products, including dimeric diketopiperazine alkaloids, monoterpenoid indole alkaloids, and iridoid glycosides, each achieved in fewer than 14 steps starting from commercially available materials.

Coumarins are widely found in medicinal plants and exhibit diverse biological properties, including antibacterial activities. Herein, we report the total synthesis of 5-geranyloxy-7-hydroxycoumarin, 5-geranyloxy-7-methoxycoumarin, and Murrayacoumarin A. The asymmetric synthesis of (+)-Murrayacoumarin A was achieved via regioselective asymmetric dihydroxylation, allowing the determination of absolute configuration at the C7'-position. In addition, the antibacterial activities of the synthesized natural products and their derivatives were evaluated.

Kakadu plum (Terminalia ferdinandiana) reportedly has the highest ascorbic acid levels of all plants worldwide and its juice reactivates functions of the retinoblastoma gene (RB) product, a tumor suppressor gene. In this study, the juice of the Kakadu plum was fractionated to identify the constituent active compounds. A novel ellagitannin, named terminalagin, was isolated from Kakadu plum (Terminalia ferdinandiana) juice via bioassay-guided isolation. The structure was determined using spectroscopic analysis and partial hydrolysis. Terminalagin has a corilagin substructure and a 2,4-(S)-hexahydroxydiphenoyl (HHDP) ester moiety that is not usually found in natural products. The results of this study enrich the structural database of ellagitannins and should provide invaluable aid for their further utilization in cancer prevention.

For the production of active pharmaceutical ingredients through sustainable organic synthesis, the use of inexpensive and non-toxic catalysts is desirable. Recently, homogeneous chiral Fe catalysts have received considerable attention as tools for achieving this goal. However, chiral Fe catalysts often perform poorly when used to synthesize complex molecules, limiting their application to large-scale syntheses. In this study, we developed an asymmetric sulfoxidation reaction for the production of esomeprazole at a pilot-plant scale. The reaction uses a catalytic system generated in situ from an Fe salt, which is abundant, inexpensive, and environmentally friendly, combined with a chiral Schiff ligand and a carboxylate salt, and hydrogen peroxide as the oxidant. Subsequently, the obtained esomeprazole is converted from its K-salt form to an Mg-salt, thereby establishing a manufacturing process that yields high-purity active pharmaceutical ingredients with impurities controlled to less than 0.05%. The enantioselectivity and kinetic resolution of the asymmetric sulfoxidation reaction are dependent on the spatial relationship between the sp³-hybridization center and the sp² carbon adjacent to the substituent attached to the S atom of the substrate. We also speculate that the carboxylic acid additive plays a critical role in activating hydrogen peroxide through heterolytic cleavage and enabling the formation of both mono- and dinuclear iron oxidants. Furthermore, we propose a catalytic mechanism for this enantioselective oxidation reaction.

Photoresponsive molecular tools have become powerful platforms for manipulating biological functions with high spatiotemporal precision. In this review, we highlight recent advances in the development of light-activated compounds that interact with key signaling molecules and microenvironments. Inspired by various chemical reactions triggered by light-matter interactions, this review covers three representative systems: photoactivatable peroxynitrite (ONOO^-) generators, visible-light-driven nitric oxide (NO) releasers, and optochemical oxygen (O₂) scavengers. ONOO^-, a reactive nitrogen species formed from NO and superoxide (O₂^-), plays a critical role in protein nitration and cellular oxidative stress. By designing molecules that generate both NO and O₂^- upon light exposure, efficient ONOO^- release was achieved and used to induce nitration reactions. For NO manipulation, the authors developed a class of photoresponsive releasers that utilize photoinduced electron transfer (PeT) to enable blue-to-red light-triggered NO release. These photoresponsive releasers allowed optical control of vasodilation both ex vivo and in vivo, which forms the basis of a minimally invasive approach to modulate blood flow. In addition, a light-responsive O₂ scavenger was developed to induce localized hypoxia in cell cultures. The light-responsive O₂ scavenger enabled optical regulation of the hypoxia-responsive pathway and activation of the transient receptor potential ankyrin 1 (TRPA1) calcium channel, which underscores the utility of this approach. Together, these studies illustrate how rational molecular design, combined with precise photochemical control, can create innovative systems for probing and directing biological events. These technologies are valuable as both a basic research tool and for potential future therapeutic applications.

The crystal structure and physicochemical properties of loxoprofen sodium dihydrate (LOX-Na 2hyd), a widely used antipyretic analgesic, were investigated. Single crystals were successfully prepared, and their structure was determined via single-crystal X-ray diffraction. The crystals featured alternating hydrophilic and hydrophobic layers: the hydrophilic layer contained water molecules and sodium ions forming coordination and hydrogen bonds, while the hydrophobic layer contained loxoprofen molecules. Thermal analysis revealed that LOX-Na 2hyd desolvated two water molecules at approximately 60°C, dehydrating into an anhydrate without passing through the amorphous state. This anhydrate reabsorbed moisture at approximately 25% relative humidity, reverting to the dihydrate form. Dynamic vapor sorption confirmed the stability of the dihydrate across a wide humidity range. The cyclopentanone ring in the LOX structure exhibited disorder, and crystallographic analysis indicated the coexistence of four stereoisomers (5R, 13R; 5S, 13S; 5R, 13S; 5S, 13R). These findings suggest structural flexibility and potential relevance for optical resolution. Because optical resolution enhances the efficacy of other drugs, such as omeprazole and ofloxacin, this study provides valuable structural insight to support similar applications for LOX. Overall, this work contributes foundational knowledge toward improving the stability and efficacy of LOX formulations through structural and physicochemical understanding.