Preparation of drug metabolites at the milligram scale is essential for determining the structure and toxicity of drug metabolites. However, their preparation using recombinant proteins and human liver microsomes (HLM) is often difficult because of technical and ethical issues. Reproducing human drug metabolism in food-derived microorganisms may be useful for overcoming these challenges. In this study, we identified an unknown metabolite of the anaesthetic drug lidocaine, which is metabolised by HLM. By screening for lidocaine metabolic activity in five types of foods (blue cheese, shiitake mushroom, natto, yoghurt, and dry yeast), we found that bacteria isolated from natto reproduced the lidocaine metabolic reaction that occurs in HLM. A fraction containing the unknown lidocaine metabolite was prepared through mass cultivation of a Bacillus subtilis standard strain, ethyl acetate extraction, open column chromatography, and HPLC purification. We identified the unknown metabolite as 3-(2,6-dimethylphenyl)-1-ethyl-2-methyl-4-imidazolidinone using NMR. Our results showed that food-derived microorganisms can produce large amounts of human drug metabolites via large-scale cultivation. Additionally, food microorganisms that can reproduce drug metabolism in humans can be used to examine drug metabolites at a low cost and without ethical issues.
Preparation of drug metabolites at the milligram scale is essential for determining their structure and toxicity. However, their preparation using recombinant proteins and human liver microsomes is often difficult because of technical and ethical issues. In this study, authors found that bacteria isolated from “natto” can produce an unknown lidocaine metabolite, which is produced by human liver microsome. Then, they prepared a fraction containing the metabolite through mass cultivation of Bacillus subtilis, then identified the metabolite by NMR. Authors demonstrated that food microorganisms can be a tool to prepare drug metabolites at a low cost and without ethical issues.
Ellagitannins, a class of polyphenols with divergent structures, have attracted considerable attention from synthetic organic chemists. The basic structures in ellagitannins contain esters of D-glucose with galloyl or hexahydroxyldiphenoyl groups, as well as diaryl ether structures. Thus, the synthesis methodologies of such components have been developed by various groups, including our group. This review describes the synthetic methods reported by our group during 2017–2023, aimed at increasing the number of ellagitannins that can be chemically synthesized. In addition, recent related reports are introduced.
This review describes the development of methodologies toward the unified synthesis of ellagitannins, a class of polyphenols with divergent structures, as reported by the Yamada group at Kwansei Gakuin University during 2017–2023. Efficient methods for constructing 3,6-O-(aR)- and 4,6-O-(aR)-hexahydroxydiphenoyl-bridged glucose moieties, in addition to various C–O digallate structures, are disclosed. The total synthesis of corilagin, mallotusinin, neostrictinin, and rugosin C is also achieved via application of the established methods, which are expected to enable increase of the number of ellagitannins that can be chemically synthesized.
Batrachotoxin (1) is a potent cardio- and neurotoxic steroid isolated from certain species of frogs, birds, and beetles. We previously disclosed two synthetic routes to 1. During our synthetic studies toward 1, we explored an alternative strategy for efficiently assembling its 6/6/6/5-membered steroidal skeleton (ABCD-ring). Here we report the application of intermolecular Weix and intramolecular pinacol coupling reactions. While Pd/Ni-promoted Weix coupling linked the AB-ring and D-ring fragments, SmI2-mediated pinacol coupling did not cyclize the C-ring. Instead, we discovered that SmI2 promoted a 1,4-addition of the α-alkoxy radical intermediate to produce the unusual 11(9→7)-abeo-steroid skeleton. Thus, this study demonstrates the convergent assembly of the skeleton of the natural product matsutakone in 11 steps from 2-allyl-3-hydroxycyclopent-2-en-1-one.
The authors previously disclosed two synthetic routes to batrachotoxin, a potent cardio- and neurotoxic steroid isolated from certain species of frogs. The manuscript reports the attempted assembly of its ABCD-ring by an alternative strategy. While Pd/Ni-promoted Weix coupling linked the AB-ring and D-ring fragments, samarium(II) iodide-mediated pinacol coupling did not cyclize the C-ring. Instead, samarium(II) iodide promoted a 1,4-addition of the α-alkoxy radical intermediate to produce the unusual 11(9→7)-abeo-steroid skeleton. Thus, this study demonstrates the convergent assembly of the skeleton of the natural product matsutakone in 11 steps from commercially available 2-allyl-3-hydroxycyclopent-2-en-1-one.
Tablets are the most commonly used dosage form in the pharmaceutical industry, and their properties such as disintegration, dissolution, and portability are influenced by their strength. However, in industry, the mixing fraction of powders to obtain a tablet compact with sufficient strength is determined based on empirical rules. Therefore, a method for predicting tablet strength based on the properties of a single material is required. The objective of this study was to quantitatively evaluate the relationship between the compression properties and tablet strength of powder mixtures. The compression properties of the powder mixtures with different plasticities were evaluated based on the force-displacement curves obtained from the powder compression tests. Heckel and compression energy analyses were performed to evaluate compression properties. During the compression energy analysis, the ratio of plastic deformation energy to elastic deformation energy (Ep/Ee) was assumed to be the plastic deformability of the powder. The quantitative relationship between the compression properties and tensile strength of the tablets was investigated. Based on the obtained relationship and the compression properties of a single material, a prediction equation was put forward for the compression properties of the powder mixture. Subsequently, a correlation equation for tablet strength was proposed by combining the values of K and Ep/Ee obtained from the Heckel and compression energy analyses, respectively. Finally, by substituting the compression properties of the single material and the mass fraction of the plastic material into the proposed equation, the tablet strength of the powder mixture with different plastic deformabilities was predicted.
This study provided the prediction equation of tablet strength of binary powder mixture with different plastic deformability. The five materials from the general pharmaceutical powders were selected based on their plastic deformability, and their compression properties were evaluated by the Heckel analysis and the compression energy analysis. The plastic deformability of the powder mixture was evaluated to estimate the tablet strength using the compression properties of powder mixture. This finding indicated that the ideal mass fraction of plastic powders to form tablets with sufficient tablet strength could be predicted from the compression properties of single material.
Hydrolysis of Electrophilic Olefins. I. Kinetic Studies on the Hydrolysis of p-Dimethylaminobenzylidene Derivatives of Active Methylene Compounds
Released on J-STAGE: March 31, 2008 | Volume 29 Issue 10 Pages 2743-2752
TSUNEJI UMEDA, EIZO HIRAI
Views: 359
Determination of Some Basic Samples in Anhydrous Acetic Acid by Complementary Tristimulus Colorimetry
Released on J-STAGE: March 31, 2008 | Volume 32 Issue 3 Pages 1011-1017
SHIGERU YOSHIDA, KAYOKO ODA, SHINGO HIROSE
Views: 359
Studies on Acetylenic Compounds. XV. Synthesis of 16-Ethynylated Steroids.
Released on J-STAGE: March 31, 2008 | Volume 8 Issue 9 Pages 815-818
Issei Iwai, Tetsuo Hiraoka
Views: 357