Chemical & pharmaceutical bulletin最新文献

Density functional theory calculations on the cyclization of di-t-butyl 2-(2-aminophenyl)-2-methyl malonate (1) to t-butyl 3-methyloxindole-3-carboxylate (2) reveal that acetic acid-assisted protonation of the carbonyl oxygen atom reduces the activation Gibbs free energy significantly lower than methanol-assisted pathways. Experimental data confirm that reaction concentration plays a pivotal role in oxindole formation. Experimental results also indicate distinct reaction mechanisms at low and high concentrations. Achieving high enantioselectivity for chiral compound 2 in high-concentration reactions requires discovering a novel chiral acid.

This study investigates the influence of needleless versus needle-based electrospinning methods on the fiber diameter of polyamide 6 (PA6) nanofibers under comparable conditions, with an emphasis on potential pharmaceutical applications. Additionally, it examines how varying solvent systems impact fiber diameter specifically in needleless electrospinning. In this study, it was found that fibers produced by the needleless method were thicker compared to those produced by the needle-based method, a trend attributable to the specific solution characteristics and parameter settings unique to this study. Notably, a 2 : 1 acetic acid : formic acid solvent mixture yielded the largest fiber diameters among the solvent systems assessed for needleless electrospinning. These results underscore the potential of PA6 nanofibers in pharmaceutical applications, suggesting that further optimization of electrospinning conditions could enhance their suitability. The study also discusses the implications of scale-up production using needleless technology, highlighting its viability for industrial applications over single-needle electrospinning.

The pharmaceutical industry relies heavily on the safe and efficient packaging of drugs and injection glass vials play a pivotal role in this regard. Ensuring the quality and consistency of these vials is essential for safeguarding the potency of pharmaceutical formulations. In this study, the recent breakthroughs achieved in the manufacturing of injection glass vials by implementing advanced surface-processing technologies were examined. We developed potential injection glass vials using the novel vial-inner-surface treatment (VIST) technology to homogenize the inner surface of the vials. Compared with common vials, the elution of alkali contents and conductivity of these injection glass vials were reduced because of the VIST technology, resulting in the formation of smooth and homogeneous inner surfaces. In addition, drug adsorption onto the inner surface of the VIST vials was considerably lowered than that onto common vials. These results suggest that VIST vials are of excellent quality and could become the standard injection glass vials.

In the present study, the stability of a supersaturated solution of indomethacin (IM) was evaluated in hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) solutions, with and without parent cyclodextrins (CDs). A highly supersaturated state of IM was maintained in the HM-HPMC solution and was further stabilized by the addition of α-CD and β-CD. Notably, the highest level of supersaturation was achieved in HM-HPMC/α-CD solution, which maintained a high concentration of IM for up to 120 h. IM concentrations in these solutions exceeded the amorphous solubility, indicating that phase separation had occurred. To explore this phase separation, Nile Red, a fluorescent probe sensitive to hydrophobic environments, was added to the supersaturated solutions. A higher fluorescence intensity was observed in the HM-HPMC/α-CD solution compared with the HM-HPMC solution, indicating a significant formation of colloidal amorphous aggregates in the supersaturated solution. Cryogenic transmission electron microscopy (Cryo TEM) analysis confirmed the presence of these aggregates, which appeared irregularly shaped. These findings suggest that the combination of HM-HPMC and α-CD effectively stabilized the colloidal amorphous aggregates in the IM supersaturated solution. The addition of α-CD facilitated the dissociation of HM-HPMC into smaller particles, increasing the number of hydrophobic stearyl moieties available for interactions with amorphous IM aggregates, thereby enhancing the stability of the supersaturated state. The combination of HM-HPMC and α-CD offers a promising approach to improving the oral bioavailability of drugs with poor water solubility.

A method for preparing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton has been developed using domino intermolecular and intramolecular S_N2 cyclization. Using this method, the formation of pyrrolidine proceeded smoothly with good yield without the E2 elimination product. This reaction condition is effective for synthesizing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton.

Here, a DNA cleavage reagent (1-(anthracen-9-ylmethyl)-1,5,9-triazacyclododecane = Ant-[12]aneN3) was designed and synthesized, and its DNA photocleavage activity under UV irradiation at λ = 365 nm was evaluated. Ant-[12]aneN3 is a molecule containing anthracene as the photosensitizer and [12]aneN3 ( = 1,5,9-triazacyclododecane) as the DNA-interacting component. The cyclic polyamine [12]aneN3 could coordinate with zinc ions (Zn^II) and affect DNA cleavage activity. Therefore, when Ant-[12]aneN3 reacted with Zn(NO₃)‧6H₂O, the product was not a Zn^II complex but an N-protonated form of Ant-[12]aneN3. In DNA cleavage experiments with the pUC19 plasmid, Ant-[12]aneN3 also showed DNA photocleavage activity in a Zn^II-independent manner. That is, [12]aneN3 enhances the DNA photocleavage activity of anthracene in a Zn^II-independent manner, unlike bpa (bis(2-picolyl)amine), which was previously reported to enhance DNA cleavage activity by chelating Zn^II. Under physiological conditions, the nitrogen atoms of [12]aneN3 appear protonated without the addition of Zn^II salts and showed an affinity for the negatively charged DNA. The results of this study may facilitate the design of effective DNA cleavage reagents.

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.

We developed a novel drug release method using a bioorthogonal inverse electron demand Diels-Alder reaction on liposomal membranes. Based on reports that replacing pyridine with pyrimidine in tetrazine derivatives improves the reaction rate with strained dienophiles, we investigated if liposomes with tetrazine derivatives containing pyrimidine rings efficiently release drugs via click chemistry. We synthesized and evaluated a tetrazine compound (Tz2) bearing a pyrimidine ring. The reaction rate constant of Tz2 with a norbornene (NB) derivative, 5-norbornenecarboxylic acid (NBCOOH), was higher than that of Tz1 with a pyridine ring. Liposomes containing the synthesized Tz2 (Tz2-liposomes) were prepared, and the reaction between Tz2 and NBCOOH on the liposomal membranes was confirmed using high-resolution mass spectrometry. We encapsulated indium-111-labeled diethylenetriaminepentaacetic acid ([¹¹¹In]In-DTPA) in liposomes as a model drug. The release of [¹¹¹In]In-DTPA from Tz2-liposomes was observed after the addition of NBCOOH, with release dependent on NBCOOH concentration. Moreover, release from Tz2-liposomes was significantly higher than that from Tz1-liposomes. These results suggested that tetrazine derivatives with pyrimidine rings efficiently released drugs, likely due to enhanced reaction rates. These findings would advance the development of controlled drug release methods using click chemistry.

Optimization of the manufacturing process based on scientific evidence is essential for quality control of active pharmaceutical ingredients. Real-time monitoring can ensure the production of stable quality crystals in the crystallization process. Raman spectroscopy is an attractive tool for pharmaceutical quality evaluation and process analytical technology because of its ability to analyze samples non-destructively and rapidly. In this study, we attempted to monitor the crystal polymorphs of carbamazepine (CBZ I and CBZ III) during the dissolution and crystallization processes using low-frequency Raman spectroscopy, which can reflect differences in lattice vibrations originating from polymorphs in the scattering peaks. Furthermore, using multivariate analysis of the obtained spectra, we attempted to develop a model that enables the quantification of each polymorph. A partial least squares was performed to build the prediction model. The prediction model was built using a set of 33 calibration samples, and an external set of 12 validation samples was used to evaluate the model. The model presents a good prediction capacity. The quantitative results for the solid amount of carbamazepine in suspension calculated using the model during the dissolution and crystallization process showed results that correlated very well with the particle view results. It is suggested that low-frequency Raman spectroscopy can be used as a useful process analytical technology tool.

Eupatilin, a natural bioactive flavone, is the active ingredient in traditional Chinese medicine Artemisia argyi Levl. et Vant. To enhance the antitumor effect of eupatilin, we designed a series of novel eupatilin-Mannich derivatives and investigated antitumor activity against several human cancer cell lines, including gastric cancer cells (AGS), esophageal cancer cells (Eca-109), and breast cancer cells (MDA-MB-231). Among all derivatives, the majority demonstrated superior antitumor activity compared to eupatilin, with compound 3d exhibiting the most effective antitumor activity against AGS cells. Furthermore, compound 3d effectively inhibited colony formation and migration of AGS cells. Network pharmacology combined with molecular docking studies indicated that compound 3d exerts antitumor activity by targeting the Hsp90AA1 and multiple signaling pathways. In addition, the Western blot experiment results showed that compound 3d reduced the expression of Hsp90AA1 in AGS cells, indicating that Hsp90AA1 may be the potential target of compound 3d. In summary, several novel eupatilin derivatives were prepared via the Mannich reaction, representing the first structure modification study of eupatilin. The mechanism of action of compound 3d was estimated through cell experiments, network pharmacology, molecular docking, and Western blot experiments, to provide lead compounds for the discovery of natural product-based antitumor candidates.