Peptides that contain unusual motifs, such as non-proteinogenic amino acids (AAs) and/or macrocyclic substructures, have recently attracted great attention as a new modality in medium-sized-molecule drug discovery. Therefore, it is highly important to develop methods for the chemical synthesis of a wide variety of such unusual peptide derivatives, which are often difficult to prepare via conventional synthetic approaches. In this review, the development of unconventional approaches for the synthesis of unusual peptide derivatives is discussed. Specifically, a novel external-oxidant-mediated decarboxylative condensation of α-ketoacids that can be applied to the synthesis of a wide variety of unusual peptide derivatives is reported. Moreover, an organocatalytic asymmetric Mannich-type addition is discussed that provides chiral β-amino-α-ketoacids, which are required as starting materials for the decarboxylative condensation. In this reaction, the adducts corresponding to various unusual AA side chains are obtained in high yield and excellent stereoselectivity. Furthermore, the “N-chloropeptide strategy” is proposed as a new method for the chemical modification of peptides without the need for a reactive AA residue.

Hyaluronan (HA) is a commonly used material in cosmetics and pharmaceuticals because of its various pharmacological activities. However, because of its large molecular weight, HA penetrates the skin very poorly and most of it remains on the skin surface. Thus, topically applied HA could not be expected to function biologically in the skin. However, we have confirmed that HA tetrasaccharides (HA4), which is the smallest unit of HA, penetrate into the skin by passive diffusion and affect epidermal metabolism. Topical treatment of HA4 rescues the epidermal damage caused by long-term UVA irradiation. Furthermore, various biological functions of HA4 to maintain healthy skin was observed in cell culture studies. This review describes the skin permeability of HA4 and how it contributes to healthy skin.

In this study we have focused on three types of alcohols: ethanol (EtOH), 2-propanol (IPA), and 1-propanol (NPA), and examined the skin permeability of drugs with different physicochemical properties: ketoprofen (KPF; hydrophobic), cimetidine (CMT; slightly hydrophobic), and caffeine (CF; hydrophilic). The results revealed EtOH particularly enhanced the skin permeation of CF, while IPA enhanced skin permeation regardless of the type of drug. In contrast, NPA significantly increased the skin permeability of KPF and CMT, but had little effect on CF. The differing effects of the alcohols on skin permeation appear to be linked to the physicochemical properties of the drugs. KPF is more hydrophobic than the other drugs, suggesting that it uses the intercellular pathway in the stratum corneum for permeation. CMT has intermediate properties between hydrophilic and hydrophobic, resulting in low skin permeability and ineffective utilization of both the transepidermal and transappendageal pathways. CF mainly utilized the transappendageal pathways for skin permeation because of its smaller molecular weight and more hydrophilic as compared with the other drugs. These results suggest that the effect of different alcohols on enhancing drug skin permeation is not uniform and that the optimal alcohol for enhancing permeability may vary depending on the drug. Therefore, the selection of appropriate additives based on the physicochemical properties of the drug, such as hydrophilicity, hydrophobicity, and molecular weight, is crucial for developing effective transdermal formulation.

The purpose of this study was to investigate the effect of the interaction between hydrophilic drugs and acrylic polymers in the adhesive layer of matrix-type patches on skin permeability. Loxoprofen is a nonsteroidal anti-inflammatory drug which has poor permeability. To improve that, patches were prepared using loxoprofen sodium hydrate (LP-Na) as the active pharmaceutical ingredient and acrylic polymers with four different functional groups with different molecular weights. In addition, to enhance the permeability of the patches, we add the lactic acid (LA) as an additive. The crystalline state of the patches was examined by polarizing microscopy and powder X-ray diffraction. The interaction between LP-Na and acrylic polymers was also evaluated using ¹H-NMR. The drug release rate and in vitro skin permeation from the patches were evaluated by dissolution apparatus (paddle method) and Franz diffusion cell, respectively. In patches using acrylic polymers with carboxy groups (AO), the skin permeation test suggested that the LP-Na_AO patch system showed 2.5 times better permeability compared with other patches. Interestingly, addition of LA (LP-Na_AO + LA) also improved 1.5 times more diffusion rate than LP-Na_AO patch and other systems. The interaction of LP-Na with acrylic polymers and LA as pH modifier would enhance the permeability of LP from matrix-type adhesive patches.

Sirtuin enzymes are interesting targets for developing new drug candidates. This study aims to design new indole-based sirtuin inhibitors, filtering through molecular docking alongside molecular dynamics and pharmacokinetic property prediction, synthesizing 4 compounds with an evaluation of their cytotoxic activity alongside the sirtuin inhibitor AGK2 against the breast cancer (MCF7) cell line via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The antibacterial activity of these compounds was evaluated by comparing the minimum inhibitory concentration (MIC) with ciprofloxacin against Staphylococcus aureus and Klebsiella pneumoniae using resazurin dye. The docking study showed a higher binding affinity for the synthesized compounds than sirtuin inhibitors AGK2 and selisistat against the sirtuin2 isoform. In addition, the molecular dynamics study showed good stability of the compound with the higher docking score in complex with sirtuin2 over 100 ns. The prediction of pharmacokinetic properties showed adherence to drug-likeness criteria. The MTT assay revealed comparable IC₅₀ values for the compounds with AGK2, as compound AFJ1 showed the highest cytotoxic activity (IC₅₀ = 2.6 μM). Among the synthesized compounds, AFJ2 showed the lowest MIC against K. pneumoniae (125 μg/mL) compared to ciprofloxacin (62.5 μg/mL).

3-Acetyl-11-keto-β-boswellic acid is a pentacyclic triterpenoid. It is found in frankincense, which is the resin found in plants from the Boswellia genus. Single crystals of 3-acetyl-11-keto-β-boswellic acid methanol and acetonitrile solvates were obtained from the Boswellia serrata extract. X-Ray crystal structure analysis revealed the coexistence of a brominated derivative, 3-acetyl-11-keto-12-bromo-β-boswellic acid. Mass spectroscopy analysis confirmed the presence of the brominated derivative in the extract. These results provide a structural basis for insights into the chemical reactivity and possibly the biosynthesis of 3-acetyl-11-keto-β-boswellic acid and its related substances in B. serrata.

Co-amorphous materials have gained special attention in the pharmaceutical field due to their high potential to enhance the oral bioavailability of poorly aqueous soluble drugs. In co-amorphous studies, few reports have examined the physical properties and molecular states of different active pharmaceutical ingredients (APIs) : co-amorphous former (CF) molar ratios and preparation methods. Therefore, we investigated the effect of molar ratio and preparation method on the physical properties of a novel co-amorphous system consisting of cilostazol and l-tryptophan, which we identified through screening. Co-amorphous consisting of molar ratios of 1 : 1 (co-milling (CM) 1 : 1), 1 : 1.5 (CM 1 : 1.5), and 1 : 2 (CM 1 : 2) were prepared by the CM method, while samples with a molar ratio of 1 : 1 (spray drying (SD) 1 : 1) were prepared by the spray drying method. CM 1 : 1.5 and CM 1 : 2 showed the highest solubility. Storage stability was excellent for CM 1:1.5, CM 1 : 2, and SD 1 : 1, whereas physical properties were improved by co-amorphization. To investigate the factors responsible for the improved physical properties, the molecular state of the co-amorphous system was evaluated, and it was inferred that hydrogen bonds were formed between cilostazol and l-tryptophan. Solid-state ¹³C-NMR showed several new peaks specific to the solid state in the co-milled sample compared to SD 1 : 1 and cilostazol amorphous, suggesting that the molecular state may differ depending on the preparation method. As described above, different physical properties and molecular states were observed in the novel co-amorphous system consisting of cilostazol and l-tryptophan when the molar ratio of APIs and CF, and the preparation method differed.

A method has been developed to suppress the formation of impurities derived from the aryl group on the phosphorus atom of the ligand used in the Suzuki–Miyaura coupling of 4-pyridineboronic acid derivatives. 4-Arylpyridine, a key substructure in several active pharmaceutical ingredients (API), is typically synthesized using this coupling reaction. However, in API synthesis, the generation of impurities derived from the aryl group on the phosphorus atom of the ligand has posed a significant challenge. In previously reported Suzuki–Miyaura coupling of 4-pyridineboronic acid derivatives, both the desired product and the aforementioned impurities were obtained. Here, we present a method to address and resolve this problem.

The δ-opioid receptor (DOR) continues to attract attention as a therapeutic target for the development of safer analgesics due to its ability to mediate pain relief with a lower risk of adverse effects compared to the μ-opioid receptor (MOR). Building upon our previous findings on KNT-127, a DOR-selective agonist with a morphinan scaffold, this study further explores the structure–signal relationships between quinoline ring modifications and the signaling bias toward Gi-protein activation while minimizing β-arrestin-2 recruitment. Our findings highlight the critical role of the 5′-position in modulating signaling bias. Bulky hydrophobic substituents, such as isopropoxy and cyclohexanoxy groups, effectively reduce β-arrestin-2 recruitment without compromising DOR binding affinity or Gi-protein activation. Molecular-docking and molecular dynamics simulations provided mechanistic insights, showing that these modifications change ligand interactions with the V281^6.55-W284^6.58-L300^7.35 sub-pocket, thus selectively favoring Gi-protein signaling. These insights clarify the key interactions for the signaling bias in DOR agonists, offering a new framework for the design of DOR-targeted therapies with an improved therapeutic profile.

The purpose of the present study was to predict the intra-individual variability (%CV_intra) values of C_max using observed parameters of physicochemical and pharmacokinetic for a variety of formulations. A database was used to summarize the parameters of clinical bioequivalence (BE) studies of oral drugs, including the highest dose tablets, orally disintegrating tablets (ODT), and capsules (278 formulations [238 compounds]). As explanatory variables, %CV_intra, inter-individual variability (%CV_inter), absolute bioavailability (BA), T_max, t_1/2, dose number (Do), and dissolution rate (D%) were selected. Explanatory variables correlated with %CV_intra were identified by multivariate analysis and grouped quantitatively by K-means clustering analysis. The %CV_intra predictions compared three models of multiple regression, boosting tree, and neural network. In the neural network, the coefficient of determination (R²) and the root mean square error (RMSE) were the best, with good correlation between the predicted and observed values of the test data (R² = 0.69). The explanatory variables used in this study are readily available from the literature of reference formulation and in vitro measurement. Therefore, predicting %CV_intra for C_max without conducting pilot studies is useful for clinical planning in the early stages of generic drug development. We believe that we could further contribute to speeding up and reducing the cost of generic drug development.

The pandemic of coronavirus disease 2019, caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a serious concern worldwide. Although some effective vaccines have been developed, only a few anti-SARS-CoV-2 drugs have been approved for their clinical use. In this study, we designed and synthesized new anti-SARS-CoV-2 drugs based on the chemical structure of amodiaquine, which is known as an antimalarial drug. Consequently, we have identified amodiaquine analogs functionalized with dialkylamino-pendant aminophenol moieties that possess a high level of anti-SARS-CoV-2 activity with a low level of toxicity.

A concise approach is presented for preparing 4ʹ-modified thymidines from oxime imidates using readily generated 4ʹ-carbon radicals. This method produces 4ʹ-modified thymidines from natural thymidine using the Mitsunobu reaction, the protection of 3ʹ-hydroxy group (when necessary), and 1,5-hydrogen atom transfer (1,5-HAT)/intermolecular 1,4-addition with electron-deficient olefins. Moreover, using a one-pot synthesis involving 1,5-HAT/intermolecular 1,4-addition, followed by the hydrolysis of the imidate intermediate under basic conditions, 4′-modified thymidine was diastereoselectively isolated. This is because the 4′-isomer transferred to the water layer in the work-up process.

5′-O-Triethylsilyl-2′-deoxy-5-azacytidine (5′-O-TesDAC) is a prodrug developed to counteract deamination by cytidine deaminase and spontaneous hydrolytic cleavage of the triazine ring. In this study, we have evaluated the physical properties of the crystal forms to determine the optimal crystal form for solid pharmaceutical development. Therefore, the crystalline morphology of 5′-O-TesDAC was assessed using terahertz spectroscopy, in addition to conventional methods (thermal analysis, powder X-ray diffraction, IR absorption spectroscopy and dynamic vapor sorption). Terahertz spectroscopy has the feature of being able to sensitively capture structural changes between lattices and molecules because the absorptions of the terahertz region correspond to those of skeletal vibrations, intermolecular vibrations, and/or lattice vibrations. For this reason, in the evaluation of crystal polymorphism, terahertz spectroscopy was considered to complement methods that have conventionally been used. Furthermore, the metastable state evaluated in this study rapidly transitions to hemihydrate at relative humidity (RH) above 10%, so it could not be measured using attenuated total reflectance-Fourier transform IR (ATR-FTIR), which is performed under atmosphere, whereas terahertz spectroscopy allowed measurements with the sample chamber exposed to dry air easily. The chemical stability was evaluated through a stability test that measured the amount of the main degradation product of each crystalline form using HPLC. As a result, four crystalline forms of 5′-O-TesDAC were identified. The characterization of 5′-O-TesDAC in this study provides valuable information for optimizing the manufacturing parameters of the formulation and selecting appropriate packaging materials for pharmaceutical development.

A squaramide organocatalyst was employed to efficiently promote asymmetric oxidative lactonization to construct spiro-fused 2-oxindoles in moderate-to-good yield and enantioselectivity (up to 81% enantiomeric excess (ee)). Herein, we report the first study accomplishing stereoselective oxidative cyclization from indole propionic acid using an organocatalyst, N-iodosuccinimide (NIS), and hydrogen peroxide under metal-free and mild reaction conditions.

This study aimed to clarify the relationship between the NMR parameters of petrolatum obtained using the time-domain NMR (TD-NMR) technique and the physical properties obtained using conventional methods. Six commercially available drug-free petrolatums were used. First, the physical properties of these samples were recorded by conventional methods: polarized light microscopy, viscometry, and X-ray diffraction (XRD). The XRD pattern showed a characteristic diffraction pattern corresponding to the crystallization of paraffin wax. Next, the TD-NMR technique estimated the solid fat content (SFC) and T₂ and T₁ relaxation times as NMR parameters. The free induction decay of petrolatum showed the characteristic biphasic decay, while the SFC value was estimated from signal intensities. Finally, a scatterplot matrix was drawn to clarify the relationship between the NMR parameters and the physical properties. Using the Spearman rank-order correlation, the SFC showed a strong and positive correlation with the crystallinity (ρ = 0.855), and the T₂ relaxation time showed a moderate and negative correlation with the viscosity (ρ = −0.707). In conclusion, this study clarified which NMR parameters correspond to the conventional physical properties: the SFC corresponded to the crystallinity and the T₂ relaxation corresponded to the viscosity. Utilization of the TD-NMR technique to evaluate molecular mobility may be useful in terms of complementing the conventional physical characterization of petrolatum.

The reaction of acetals with trialkylsilyl chloride (R₃SiCl) leads to the deprotection of the acetal group, resulting in the corresponding carbonyl compounds. Notably, aromatic dialkyl acetals yield the corresponding parent aromatic aldehydes and ketones in good yields. The reaction conditions are very mild, allowing many acid-labile functional groups to survive without any problems. Additionally, we clarified the reaction mechanism through an NMR study.

Silibinin is the major active constituent of the medicinal plant milk thistle seeds and possesses hepatoprotective functions. In this study, silibinin A was irradiated with gamma rays to produce 2 novel flavonolignans, silibinosins A (2) and B (3). The structures of these compounds were determined using spectroscopy and spectrometry. The anti-inflammatory effects of the flavonolignan derivatives were assessed using lipopolysaccharide (LPS)-stimulated RAW264.7 and DH82 macrophages. Silibinosin A (2) effectively suppressed the LPS-induced overproduction of pro-inflammatory mediators and cytokines in murine RAW264.7 cells. Western blot analysis revealed that compound 2 decreased the LPS-induced expression of inducible nitric oxide synthase, cyclooxygenase, and phosphorylated nuclear factor-κB and inhibitor-κBα compared to the original silibinin. Furthermore, the inhibitory effects on nitric oxide and prostaglandin E₂ production were observed in LPS-stimulated DH82 canine macrophages. Our results suggest that the newly generated flavonolignans can be novel anti-inflammatory agents for use as therapeutics or ingredients in functional foods.

Estrogen receptors (ERs) and their ligands regulate a variety of physiological processes in humans, and altered ER signaling is associated with serious disorders, including breast cancer. Estrogens also bind to other receptors such as G-protein-coupled receptor 30 (GPER), and so fluorescent estrogen ligands would be useful for various functional studies and for development of drug candidates. Here we describe fluorescent estrogen receptor ligands based on 3-aryl-7-hydroxycoumarin. Notably, these ligands also function as pH-dependent OFF-ON-OFF type fluorescent sensors, enabling the detection of specific ranges of pH.