A method for chemoselective acylation of the vacant amide of diketopiperazines (DKPs) using di-tert-butyl dicarbonate (Boc₂O) was developed. Nucleophilic tributylphosphine reacts immediately with acid anhydride to form an active quaternary phosphonium cation. This intermediate induces acylation of the amide group on the empty side, resulting in chemoselectivity that could not be controlled by using N,N-dimethyl-4-aminopyridine (DMAP). This method achieved high yields of mono-acylated DKPs, avoiding the acylation of amino acids with bulky substituents. This reaction system also provides chemoselectivity based on the bulkiness of the protecting groups of active functional groups at the side chain, and enhances the range of substrate applicability by achieving acylation of the amido groups of amino acids, except for glycine. Furthermore, using the substrates prepared here, elongation reactions induced by introducing amino acid esters associated with ring opening were also successfully demonstrated under reaction conditions without any additives, highlighting the possibility to form peptides with a broad range of sequences.

Furanosteroids are known to exhibit inhibitory activity against phosphatidylinositol-3-kinase and are expected to serve as a basis for the development of therapeutic drugs for various diseases. In this study, a novel protocol is presented for preparation of the furanosteroid A-ring moiety. More specifically, the lipase-catalyzed kinetic resolution of racemic 1-(3-bromofuran-2-yl)-2-chloroethanol with β-substituted (Z)-acrylates and the subsequent intramolecular Diels–Alder reaction of the generated enantiomerically enriched esters were performed to obtain multi-functionalized fused cyclohexenes in excellent enantiomeric ratios (99 : 1 or 98% enantiomeric excess (ee)) and diastereomeric ratios (≥98 : 2). The obtained products possess the appropriate stereochemical structures and absolute configuration for use in the asymmetric synthesis of the A-ring moieties of naturally occurring furanosteroids, including viridin and viridol.

[5-(3-Chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl] acetonitrile (S-892216) is a small-molecule compound developed by Shionogi & Co., Ltd. as a 2nd-generation 3CLpro inhibitor against severe acute respiratory syndrome coronavirus 2. In this study, we evaluated the feasibility of developing a long-acting injectable suspension formulation of S-892216 for the future development of a coronavirus disease 2019 pre-exposure prophylaxis medicine for immunocompromised patients. We found that the S-892216 drug substance had a low solubility, suitable for long-acting injectable suspension development. The developed S-892216 injectable suspension showed prolonged plasma exposure in both rats and beagle dogs when formulated as a nanosuspension. Selecting polysorbate 20 as a stabilizer enabled the manufacturing of the nanosuspension with less wet-milling time than that required for poloxamer P338. The developed injectable suspension was stable for 12 months at 5 and 25°C/60% relative humidity after terminal sterilization by gamma irradiation. Thus, the developed injectable suspension shows potential for further development for human use.

Oxyluciferin is the key photon emitter in the firefly/beetle luciferase-catalyzed bioluminescence reaction, and elucidating its chemical form within the active site of luciferase is essential for understanding and modulating emission wavelength. In this study, we focused on aminoluciferin (AL), a d-luciferin (d-LH₂) analog in which the hydroxy group is substituted with an amino group. AL has been widely used as an alternative substrate to d-LH₂ and in the development of bioluminescence probes. To identify the emissive form of AL in bioluminescence, we synthesized OxyAL (the emitter derived from AL) and 5-methyl-OxyAL, and measured their fluorescence spectra under various conditions. We assigned the range of emission wavelengths of keto-, enol- and enolate-OxyAL using 5,5-dimethyl-OxyAL, fixed in the keto form, as a reference. Based on spectral assignments and comparison with the bioluminescence spectra of AL, we conclude that enolate-OxyAL is the most probable light-emitting species in the active site of luciferase. These findings provide new insight into AL-based bioluminescence.

Pyrroloindolines are promising compounds, yet reports on their syntheses remain scarce. Herein, we report the diastereoselective synthesis of C3a-arylated pyrroloindolines bearing substituents on the pyrrolidine ring by a facile palladium–dihydroxyterphenylphosphine-catalyzed C3-dearomative arylation of substituted tryptamine derivatives, followed by the intramolecular cyclization of the resulting indolenine. The reaction with various tryptamine derivatives showed that the position and bulkiness of the substituents on the aminoethyl chain of the tryptamines strongly influenced the site- and diastereoselectivity of the arylation. The steric hindrance of the arylating agents also determined the reactivity and diastereoselectivity. This study presents an efficient diastereoselective method to synthesize pyrroloindolines with C3a-aryl groups from widely available substituted tryptamine derivatives.

Bicarbonate buffer (BCB) has been difficult to use in conventional dissolution tests because its pH rapidly increases as CO₂ escapes from the air–water interface. Recently, the floating lid method was introduced as a convenient method for using BCB in dissolution tests. This study aimed to confirm the inter-laboratory reproducibility of pH maintenance of BCB using the floating lid method for both paddle and flow-through cell (FTC) methods. Three pharmaceutical companies and 1 academic research institute participated in this study. A BCB solution (pH 6.5, 15 mM) was employed as the test solution. In the paddle method, the pH values of BCB rapidly increased without the floating lid. The pH change (ΔpH) at 6 h ranged from +1.66 to +1.82 (50 rpm) and +1.96 to +2.02 (100 rpm). The floating lid effectively maintained the pH values in all laboratories, with ΔpH ranging from +0.13 to +0.17 (50 rpm) and +0.21 to +0.25 (100 rpm). The standard deviation of ΔpH was within 0.05 at both 50 and 100 rpm. Similarly, in the FTC method, without the floating lid, ΔpH ranged from +1.71 to +1.77 (reservoir), +1.59 to +1.72 (FTC), and +1.73 to +1.76 (sampling tube). With the floating lid, ΔpH ranged from +0.05 to +0.10 (reservoir), +0.05 to +0.09 (FTC), and +0.26 to +0.39 (sampling tube). The standard deviation of ΔpH was within 0.05. In conclusion, the inter-laboratory reproducibility of pH maintenance of BCB using the floating lid method was confirmed for both the paddle and FTC methods.

Bisenarsan is an organoarsenic natural product identified from actinomycetes and a derivative of (2-hydroxyethyl)arsonic acid (2-HEA) esterified with 2,4,6-trimethyl-2-nonenoic acid (2,4,6-TMNA). Our previous study suggested that bisenarsan is biosynthesized from arsenate [As(V)] via arsonoacetaldehyde (AnAA). In contrast, the late-stage biosynthetic steps from AnAA to bisenarsan and the roles of transporter genes within the biosynthetic gene clusters (BGCs) of bisenarsan remain unclear. In this study, through in-frame deletions and heterologous expression targeting the bisenarsan BGC in Streptomyces lividans 1326 (bsn cluster), we identified bsnF (nicotinamide adenine dinucleotide phosphate-dependent oxidoreductase), bsnPKS (iterative type I polyketide synthase), and bsnFB (3-ketoacyl-acyl carrier protein synthase III family protein) as genes encoding enzymes likely responsible for the late-stage biosynthesis of bisenarsan. BsnF, BsnPKS, and BsnFB are presumed to catalyze the reduction of AnAA to 2-HEA, the formation of the 2,4,6-TMNA moiety, and the ester bond formation, respectively. Furthermore, based on the functional analysis of the transporter genes in the bsn cluster, BsnT2 (major facilitator superfamily transporter) appears to be involved in the efflux of bisenarsan. Although the roles of other transporters in bisenarsan biosynthesis remain unclear, they may contribute to the uptake and efflux of inorganic arsenic, presumably to ensure a consistent substrate supply and mitigate toxicity caused by its overaccumulation. Our study provides valuable insights into the biosynthesis of a rare class of organoarsenic natural products, with arsonopyruvate as an intermediate.

Prealnumycin B is an aromatic polyketide characterized as a reduced form of prealnumycin with a 6S-alcohol. As an extension of our earlier work on the synthesis of prealnumycin, the C7–C8 double bond was hydrogenated using Wilkinson’s catalyst, and the C6 carbonyl group was stereoselectively reduced via asymmetric transfer hydrogenation with the (S,S)-Ts-DENEB catalyst, where the use of methanol as a solvent was crucial for achieving high regioselectivity. By comparing its spectroscopic data with those of the natural isolate, the absolute configuration of prealnumycin B was determined to be 1R,6S. In addition, the antibacterial activities of prealnumycin B and related compounds were evaluated.

This study aims to employ molecular dynamics (MD) methods to predict the miscibility and molecular interactions between loratadine (LOR) and polymers, thereby designing drug formulations with enhanced water solubility. The research seeks to improve formulation design efficiency and accelerate the drug development process. A viable approach to enhance the solubility of poorly soluble drugs involves creating solid dispersions (SDs) with hydrophilic polymers. However, the specific intermolecular interactions within this system warrant further investigation. In this study, MD simulations were conducted to assess the molecular miscibility and interactions between LOR and 4 polymers. Then, the simulation results were verified by physical experiments. The findings demonstrate that LOR exhibits substantial miscibility with these polymers. Among the 2 drug loading ratios, S4 and S7 exhibited the strongest interactions, respectively. The solubility experiment also confirmed this result. It is confirmed that MD can be used to predict the formation of SDs, and this method can also predict the water solubility of the system, underscoring the utility of MD in advancing the development of SDs.

Dopamine, a catecholamine neurotransmitter found in both neural tissue and body fluids, plays a critical role in brain function. Its distribution in specific brain regions affects the coordination of pituitary endocrine functions and is directly involved in neural activities, making dopamine concentration detection vital. In this study, highly fluorescent silicon quantum dots (silicon nanoparticles: SiNPs) were synthesized and employed as a fluorescent probe for convenient dopamine detection in Tris buffer. This detection mechanism relies on dopamine’s self-polymerization, which results in polydopamine absorbing and quenching the fluorescence of SiNPs through a clarified inner filter effect in a concentration-dependent manner. Under optimized experimental conditions, the method demonstrated a robust linear relationship between the fluorescence quenching efficiency of SiNPs and dopamine concentration (C_DA) within the range of 0.5–40 μM. The linear equation was found to be Y = 0.0074 C_DA + 0.0142, with a limit of detection of 0.06 μM. Moreover, the method was successfully applied to detect dopamine in injection solutions and serum samples, offering a sensitive and selective approach for dopamine detection with promising potential for practical applications.

Ruthenium–vinylidene intermediates derived from ynamides show great promise for synthesizing nitrogen-containing heterocycles. Azepinoindoles are significant in medicinal chemistry owing to their varied biological activities. Different azepinoindole frameworks feature diverse fused arrays of indole and azepine rings. In this study, we introduce a ruthenium-catalyzed approach based on ynamide chemistry to produce various azepinoindole frameworks using ynamides with an indole unit. Mechanistic insights were obtained through deuterium labeling experiments.

We report the catalyst-free aminoalkylation of alkenes, enabled by the formation of an electron donor–acceptor (EDA) complex between alkenes and amine-tethered N-hydroxyphthalimide (NHPI) esters. This visible-light induced transformation proceeds without external photocatalysts or additives. Spectroscopic and computational analyses support EDA complex formation, which undergoes photoinduced single-electron transfer to generate a radical ion pair that initiates C–N bond formation via intramolecular cyclization. The reaction exhibits a broad substrate scope, including electron-rich and electron-deficient alkenes, as well as structurally diverse NHPI esters, enabling access to various nitrogen-containing heterocycles such as pyrrolidines, benzodioxoles, and furan-fused frameworks. This operationally simple and modular method is a valuable platform for constructing biologically relevant molecules under mild conditions.

Current methods for evaluating the photostability of pharmaceutical drugs typically separate the irradiation step from the analytical process, making it challenging to observe real-time photodegradation during irradiation. The use of HPLC equipped with UV and/or MS detectors, which are commonly used for quantitative analysis, requires considerable time to establish optimal conditions, and employs organic solvents, which are harmful to both the environment and the analyst. The aim of this study is to investigate the effectiveness of isothermal differential scanning calorimetry (DSC) equipped with a UV probe (photo-DSC) for evaluating the photostability of pharmaceutical drugs in the solid state. The response to light irradiation varies for different drugs, with some drugs exhibiting a thermal history showing endothermic behavior. To confirm the results of the endothermic reaction in photo-DSC, the percentage of the drug remaining after photo-irradiation was quantified using HPLC. Drugs that exhibited endothermic peaks consistently showed a decrease in residuals due to the photolysis reaction. In this study, we highlight the effectiveness of photo-DSC in evaluating the susceptibility of different drugs to photodegradation.

The (ammonio)amidyl (AA) groups, with the general structure of R₃N⁺N⁻–, represent a new class of π-electron-donating groups for the benzene-based π-conjugated molecules. This study investigated AA-substituted p-nitrobenzenes to assess the effects of acyclic, monocyclic, and bicyclic ammonium structures in the AA groups on the π-electron-donating ability and thermal stability of the structure. Quantum chemical calculations were performed that supported the experimentally observed favorable properties of the (quinuclidinio)amidyl (QA) group.