A total synthesis of javaberine A was achieved through a lithium amide-mediated intramolecular hydroamination of an N-allyl aminoalkene. The desired hydroamination was accomplished using an excess of i-Pr₂NH with a substoichiometric amount of n-BuLi. Using an excess of both n-BuLi and i-Pr₂NH led to tandem cyclization, however, resulting in the construction of a tricyclic structure through the formation of one C–N and two C–C bonds in a single operation. Additionally, epimerization of the H8-H14 cis-benzyl tetrahydroisoquinoline to the trans isomer was achieved via β-elimination followed by intramolecular hydroamination.

Pharmaceutical packaging is essential for enhancing the storage stability of medicine and can improve medication adherence and usability. Despite their widespread use, blister packs can be challenging to use, especially when pushing out the medication. This study investigates how specific cavity characteristics of blister packs can enhance usability for spherical capsules, which are harder to push out than tablets. The findings of this study show that reducing the thickness of the unformed sheet, or the thickness at the top and corners of the cavities, reduces the effort required to push out the capsules. Similarly, for cavities with different shapes, reducing the thickness at the top and increasing the corner radius also eases the push-out process. These insights emphasize the importance of systematic design in pharmaceutical packaging to improve patient medication adherence.

The main ingredients of Maobushisaishinto (MBST) are ephedrine (EP), methyl eugenol (ME), and aconitine (AC). The pharmacological effects are presumed to be due to the combined effects of these ingredients. In this study, we investigated the impact of the particles present in MBST suspensions on the absorption of the ingredients. Coarse, colloidal, and molecular dispersions were detected when MBST was dispersed in water at 25 and 70 °C. Regardless of temperature, the ratio of MBST in molecular dispersions was the highest, and the ratio of coarse dispersions was greater than that of colloidal dispersions. Particles ranging from 50 to 900 nm were observed in the colloidal dispersions prepared by treatment at 25 °C for 3 min. However, in 70 °C water, the mean particle size decreased, and the number of nanoparticles tended to increase. The levels of EP, ME, and AC in molecular dispersions were higher than those in coarse and colloidal dispersions, with no significant difference observed between the coarse and colloidal dispersions. On the other hand, in small intestinal penetration, the levels of EP, ME, and AC in colloidal dispersions were higher than those in the other two dispersions. Moreover, adding colloidal particles to the dissolved drug (molecular dispersions) increased the drug’s permeability through the small intestinal membrane. In conclusion, colloidal particles are produced when MBST is suspended. Furthermore, we showed that these colloidal particles enhance the absorption of the main ingredients of MBST.

We have investigated the base-induced long-range halogen dance reactions of 4,5-dibromo- or 4-bromo-5-iodothiazoles bearing sulfur-containing aromatic heterocycles at the C2-position. We have found that the reaction occurs in bithiazole regioisomers or (thiophenyl)thiazole derivatives, in which the C-5 halo group on the thiazole halogen donor regioselectively migrates to a halogen acceptor ring after treatment with lithium bis(trimethylsilyl)amide. The substrate with a thiophen-2-yl substituent required highly basic P₄-t-Bu to induce the halogen dance reaction.

Enteric-coated microcapsules can protect roxithromycin (ROX) from acid hydrolysis enhancing efficacy, solubility, and dissolution rate, representing a promising oral formulation for children and patients with swallowing difficulties. ROX-layered core particles were obtained with polyvinylpyrrolidone (PVP) K30 as the binder and Eudragit L30 D-55 as the coating material using the Wurster process in a fluidized bed processor. The enteric-coated microcapsules were characterized using powder X-ray diffraction, differential scanning calorimetry, and polarized optical microscopy. Enteric microcapsules with appropriate coating levels and particle sizes underwent dissolution tests, acid resistance tests. The weight ratio of PVP K30 to ROX was 1/2, and the average particle size of ROX-layered core particles was 130 µm. ROX molecule crystallinity in the layered core particles was inhibited. ROX was dispersed in PVP K30 with small particle size and high wettability. The average particle size of ROX enteric microcapsules with 60% coating level was approximately 155 µm. The acid resistance test showed that enteric microcapsules with a coating level of >50% and plasticizer contents of 20–25% can effectively protect ROX stability in simulated gastric fluid within 2 h. The dissolution experiment showed that the enteric microcapsules could protect ROX under acidic conditions of pH 1.2 and released >75% of ROX in the simulated intestinal fluid at pH 6.8 in 45 min. The enteric microcapsule of ROX using Wurster fluidized bed method can protect ROX from acid hydrolysis to ensure the efficacy, and has potential application in pharmaceutical industries, owing to its favorable dissolution.

A co-amorphous state composed of probucol (PC) and fluvastatin sodium salt (FLU) was prepared by spray-drying (SD). We have previously reported that PC and atorvastatin calcium trihydrate salt (ATO) formed a co-amorphous state when prepared by a SD method and that the solubility of PC and the amorphous stability were improved by the preparation of the co-amorphous state. In the present study, the physicochemical properties, including the amorphous stability of the prepared co-amorphous state, were characterized. Powder X-ray diffraction measurement results suggested that PC and FLU formed a co-amorphous state and that a higher percentage of PC was dissolved from the PC–FLU co-amorphous state than from the PC–ATO co-amorphous state. The results are attributed to FLU exhibiting greater solubility and wettability than ATO, which is supported by the results of solubility tests and contact-angle measurements. The stability of the amorphous state of PC is higher in the co-amorphous state with ATO than in that with FLU. This difference is attributed to differences in the molecular interaction modes between PC–FLU and PC–ATO. Therefore, the selection of high-wettability molecules as a co-former for the co-amorphous state enhances its water solubility. The present study also indicates that molecular interactions enhance the stability of the co-amorphous state.

Osteoporosis is treated with oral and parenteral resorption inhibitors and parenteral osteogenic drugs. However, orally active small-molecule osteogenic drugs are not clinically available. Natural coumarin derivatives, such as osthole, exert osteoblastogenic effects. In the present study, novel 4,6-substituted coumarin derivatives were synthesized, and their osteoblastogenic effects were assessed in a bone mesenchymal stem cell line (ST2 cell), and structure–activity relationships were discussed. Among the derivatives tested, the osteoblastogenic effects of 2-oxo-4-[4-(tetrahydro-2H-pyran-4-yloxymethyl)phenyl]-2H-chromene-6-carboxamide (11m) and 2-oxo-4-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2H-chromene-6-carboxamide (29v) were potent: EC₂₀₀ for increasing alkaline phosphatase (ALP) activity were 34 and 24 nM, respectively. The maximal plasma concentrations (C_max) of 11m and 29v (10 mg/kg, per os (p.o.)) in female rats were 3637 and 975 nM, respectively, resulting in high C_max/EC₂₀₀ ratios of 105.9 and 40.8, respectively, indicating possible osteoblastogenic effects in vivo. Compound 11m (10 mg/kg, p.o., 8 weeks) was previously reported to increase plasma bone-type ALP activity as well as femoral metaphyseal and diaphyseal cortical bone volumes and mineral contents in micro-computed tomography analyses of ovariectomized female rats (OVX rats). Compound 29v at the same dose also exerted osteoblastogenic and osteogenic effects in OVX rats; however, these effects were weaker than those of 11m. Furthermore, 11m and 29v inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that their osteoblastogenic effects involved the suppression of CDK8. In conclusion, a synthetic 4,6-substituted coumarin structure is a useful scaffold for osteoblastogenic and osteogenic compounds via the inhibition of CDK8, and 11m and 29v have potential as anti-osteoporotic drugs that exert osteogenic effects on cortical bone.

Sesame (Sesamum indicum L.) is an important oilseed crop, and its seeds are a source of edible oil and widely used as a nutritious food that is beneficial to health in oriental countries. Phytochemical and biological investigations of the seeds have been well reported; however, those of the leaves have been limited. To explore the potential value of sesame leaves, we focused on their antihypertensive potency. Oral administration of sesame leaf extract significantly reduced blood pressure in spontaneously hypertensive rats. Next, we examined the angiotensin I-converting enzyme (ACE)-inhibitory activity of sesame leaves, stems, and seeds and observed that the inhibitory potencies of leaves and seeds were stronger than those of stems. Acteoside and pedaliin, the major compounds in the leaves, as well as exhibited ACE inhibitory activity. Furthermore, we determined the content of these compounds in the leaves, stems, and seeds using LC/MS. The contents of both compounds in the leaves were higher than those in the stems and seeds. These results suggest that sesame leaf extract can mitigate hypertension, at least in part, via the inhibition of ACE activity by acteoside and pedaliin, suggesting that sesame leaves may have the potential to be used for treating hypertension.

In the present study, an algae-containing octocoral, Junceella fragilis, was subjected to chemical screening. The analysis resulted in the extraction of six polyacetoxybriaranes: a new compound, identified as fragilide Z (1), alongside previously identified analogs, which included 12-epi-fragilide G (2), fragilide P (3), junceellolide D (4), junceellonoid A (5), and juncin ZI (6). The structures of compounds 2–6 were investigated through single-crystal X-ray diffraction analysis, whereas that of 1 was examined through two-dimensional nuclear magnetic resonance analysis. Compounds 1–6 proved active in enhancing the growth of MG-63 human mesenchymal stem cells.