A noise filter, which is usually attached to a detector for chromatography, was applied for the improvement of a signal-to-noise ratio (S/N) on a chromatogram. The objective of this paper is to elucidate the effect of noise filtering in an UV detector of ultra HPLC (UHPLC) on the statistical reliability of chemometrically evaluated repeatability by the function of mutual information (FUMI) theory. To examine the statistical reliability of chemometrically evaluated repeatability in the UHPLC system associated with noise filtering, the standard deviation (SD) values of the area in baseline fluctuations with peak region k (s(k)) were obtained from six chromatograms with noise filtering. Further, the average of s(k) values (σ̂) was calculated from the s(k) values (n = 6) to be alternatively applied as the population SD. All s(k)/σ̂ values were within the 95% confidence intervals (CIs) at the freedom degree of 50, indicating the chemometrically estimated relative SD (RSD) of a peak area and RSD by repeated measurements of at least 50 times had equivalent reliability.
{"title":"Effect of Noise Filtering in an Ultraviolet Detector of UHPLC on the Statistical Reliability of Chemometrically Evaluated Repeatability.","authors":"Akira Kotani, Koichi Machida, Ryo Watanabe, Hideki Hakamata","doi":"10.1248/cpb.c24-00393","DOIUrl":"https://doi.org/10.1248/cpb.c24-00393","url":null,"abstract":"<p><p>A noise filter, which is usually attached to a detector for chromatography, was applied for the improvement of a signal-to-noise ratio (S/N) on a chromatogram. The objective of this paper is to elucidate the effect of noise filtering in an UV detector of ultra HPLC (UHPLC) on the statistical reliability of chemometrically evaluated repeatability by the function of mutual information (FUMI) theory. To examine the statistical reliability of chemometrically evaluated repeatability in the UHPLC system associated with noise filtering, the standard deviation (SD) values of the area in baseline fluctuations with peak region k (s(k)) were obtained from six chromatograms with noise filtering. Further, the average of s(k) values (σ̂) was calculated from the s(k) values (n = 6) to be alternatively applied as the population SD. All s(k)/σ̂ values were within the 95% confidence intervals (CIs) at the freedom degree of 50, indicating the chemometrically estimated relative SD (RSD) of a peak area and RSD by repeated measurements of at least 50 times had equivalent reliability.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As an easy-to-handle reagent for the in situ generation of outstandingly electrophilic Tf2C=CH2 (Tf=CF3SO2), we have designed and synthesised a novel 4-substituted 2-fluoropyridinium zwitterion, in which a partially fluorinated alkyl group is attached to the pyridinium 4-position. Its zwitterionic nature has been well characterised by quantum chemical bonding analysis. By using this reagent, a wide variety of organic compounds, including commercial bioactive agents, were successfully decorated by the strongly acidic or ionic functionality. Remarkably, the 4-substituted 2-fluoropyridine derivative, which results from the zwitterion with the generation of Tf2C=CH2, can be rapidly separated and recovered from the reaction mixture appropriately using distillation, organic solvent extraction, or fluorous solid phase extraction techniques. Such multi-optionality for the purification methods favours in the isolation of the strongly acidic and/or ionic products.
{"title":"Recyclable 2-Fluoropyridine Derivative as a Storage for Highly Electrophilic 1,1-Bis(triflyl)ethylene.","authors":"Hikaru Yanai, Shoki Hoshikawa, Hiromu Watanabe, Hiroshi Kaneko, Hidemasa Nakaminami, Takashi Matsumoto","doi":"10.1248/cpb.c24-00499","DOIUrl":"https://doi.org/10.1248/cpb.c24-00499","url":null,"abstract":"<p><p>As an easy-to-handle reagent for the in situ generation of outstandingly electrophilic Tf<sub>2</sub>C=CH<sub>2</sub> (Tf=CF<sub>3</sub>SO<sub>2</sub>), we have designed and synthesised a novel 4-substituted 2-fluoropyridinium zwitterion, in which a partially fluorinated alkyl group is attached to the pyridinium 4-position. Its zwitterionic nature has been well characterised by quantum chemical bonding analysis. By using this reagent, a wide variety of organic compounds, including commercial bioactive agents, were successfully decorated by the strongly acidic or ionic functionality. Remarkably, the 4-substituted 2-fluoropyridine derivative, which results from the zwitterion with the generation of Tf<sub>2</sub>C=CH<sub>2</sub>, can be rapidly separated and recovered from the reaction mixture appropriately using distillation, organic solvent extraction, or fluorous solid phase extraction techniques. Such multi-optionality for the purification methods favours in the isolation of the strongly acidic and/or ionic products.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Twisted intramolecular charge transfer (TICT) is a phenomenon involving intramolecular charge transfer together with intramolecular rotation upon photoexcitation, and in general this excited state of fluorescent dyes undergoes non-radiative decay (producing no fluorescence). We recently discovered that the magnitude of TICT in rhodamine derivatives could be regulated by altering the size of the substituents on the xanthene moiety, generating differing degrees of intramolecular steric repulsion. To further illustrate the usefulness and generality of this strategy, we describe here an application of quinone methide chemistry, which is widely used as a fluorescence off/on switching reaction for fluorescence probes detecting enzymatic activity, to construct a steric repulsion-induced (sr)-TICT-based fluorescence probe targeting nitroreductase (NTR) activity. The developed probe was almost non-fluorescent in phosphate-buffered saline (PBS) due to strong induction of the TICT state. On the other hand, when the probe was incubated with NTR and nicotinamide adenine dinucleotide (NADH), a large fluorescence increase was observed over time. We confirmed that the enzymatic reaction proceeded as expected, i.e., the nitro group of the probe was reduced to the corresponding amino group, followed by spontaneous elimination of iminoquinone methide. These results suggest that our simple design strategy based on the sr-TICT mechanism, i.e., controlling intramolecular steric repulsion, would be applicable to the development of fluorescence probes for a variety of enzymes.
{"title":"Development of a Fluorescence Probe for Detecting Nitroreductase Activity Based on Steric Repulsion-Induced Twisted Intramolecular Charge Transfer (sr-TICT).","authors":"Mizuki Sugimoto, Eita Sasaki, Hisashi Ohno, Takayuki Ikeno, Sota Yamada, Kenjiro Hanaoka","doi":"10.1248/cpb.c24-00486","DOIUrl":"10.1248/cpb.c24-00486","url":null,"abstract":"<p><p>Twisted intramolecular charge transfer (TICT) is a phenomenon involving intramolecular charge transfer together with intramolecular rotation upon photoexcitation, and in general this excited state of fluorescent dyes undergoes non-radiative decay (producing no fluorescence). We recently discovered that the magnitude of TICT in rhodamine derivatives could be regulated by altering the size of the substituents on the xanthene moiety, generating differing degrees of intramolecular steric repulsion. To further illustrate the usefulness and generality of this strategy, we describe here an application of quinone methide chemistry, which is widely used as a fluorescence off/on switching reaction for fluorescence probes detecting enzymatic activity, to construct a steric repulsion-induced (sr)-TICT-based fluorescence probe targeting nitroreductase (NTR) activity. The developed probe was almost non-fluorescent in phosphate-buffered saline (PBS) due to strong induction of the TICT state. On the other hand, when the probe was incubated with NTR and nicotinamide adenine dinucleotide (NADH), a large fluorescence increase was observed over time. We confirmed that the enzymatic reaction proceeded as expected, i.e., the nitro group of the probe was reduced to the corresponding amino group, followed by spontaneous elimination of iminoquinone methide. These results suggest that our simple design strategy based on the sr-TICT mechanism, i.e., controlling intramolecular steric repulsion, would be applicable to the development of fluorescence probes for a variety of enzymes.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kenichi Matsuda, Shinya Niikura, Rintaro Ichihara, Kei Fujita, Anna M Strasser, Rokusuke Yoshikawa, Jiro Yasuda, Yoshiki Hiramatsu, Hironori Hayashi, Eiichi N Kodama, Toshiyuki Wakimoto
Surugamides are a group of non-ribosomal peptides produced by Streptomyces spp. Several derivatives possess acyl groups, which are proposed to be attached to a lysine side chain after backbone-macrocyclization during biosynthesis. To date, five different acyl groups have been identified in nature, yet their impacts on biological activity remain underexplored. Here we synthesized surugamide B derivatives with varied acyl moieties. Biological evaluations revealed that larger hydrophobic acyl groups on lysine ε-NH2 enhance cytotoxicity.
苏鲁酰胺是由链霉菌属(Streptomyces spp)产生的一类非核糖体肽,其中几种衍生物具有酰基,据推测,酰基是在生物合成过程中经过骨架大环化后连接到赖氨酸侧链上的。迄今为止,已在自然界中发现了五种不同的酰基,但它们对生物活性的影响仍未得到充分探索。在此,我们合成了具有不同酰基的素酰胺 B 衍生物。生物学评价显示,赖氨酸 ε-NH2 上较大的疏水酰基增强了细胞毒性。
{"title":"Synthesis and Cytotoxicity of Cyclic Octapeptide Surugamides with Varied N-Acyl Moieties.","authors":"Kenichi Matsuda, Shinya Niikura, Rintaro Ichihara, Kei Fujita, Anna M Strasser, Rokusuke Yoshikawa, Jiro Yasuda, Yoshiki Hiramatsu, Hironori Hayashi, Eiichi N Kodama, Toshiyuki Wakimoto","doi":"10.1248/cpb.c24-00533","DOIUrl":"10.1248/cpb.c24-00533","url":null,"abstract":"<p><p>Surugamides are a group of non-ribosomal peptides produced by Streptomyces spp. Several derivatives possess acyl groups, which are proposed to be attached to a lysine side chain after backbone-macrocyclization during biosynthesis. To date, five different acyl groups have been identified in nature, yet their impacts on biological activity remain underexplored. Here we synthesized surugamide B derivatives with varied acyl moieties. Biological evaluations revealed that larger hydrophobic acyl groups on lysine ε-NH<sub>2</sub> enhance cytotoxicity.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monoammonium glycyrrhizic acid (MAG), a glycyrrhizic acid monoammonium salt, is a naturally derived low-molecular-weight gelling agent with surface-active properties. It has the capacity to individually facilitate the preparation of gel-solubilized drugs. As MAG is an anionic surfactant with carboxyl groups, the addition of counterions may affect micelle formation and gelation. In this study, the solubilization and gelling properties of MAG were investigated following the addition of metal salts (NaCl and KCl). The addition of metal salts resulted in a decrease in the critical micelle concentration and an increase in gel hardness. Supersaturation of curcumin (CUR) was maintained by the addition of metal salts because of increased micelle number and viscosity. When the gel hardness was compared between formulations with and without CUR, a significant reduction in hardness was observed with the solubilization of CUR. The addition of KCl prevented the decrease in the hardness of gels containing CUR compared to the addition of NaCl. Put together, the addition of metal salts had a noteworthy impact on micelle and gel formation of MAG. In particular, the addition of KCl was more effective in the preparation of gel-solubilized CUR.
甘草酸单铵盐(MAG)是一种天然提取的低分子量胶凝剂,具有表面活性特性。它能够单独促进凝胶溶解药物的制备。由于 MAG 是一种带有羧基的阴离子表面活性剂,添加反离子可能会影响胶束的形成和凝胶化。本研究考察了 MAG 在添加金属盐(NaCl 和 KCl)后的增溶和胶凝特性。添加金属盐后,临界胶束浓度降低,凝胶硬度增加。由于胶束数和粘度增加,姜黄素(CUR)的过饱和度在添加金属盐后得以维持。在比较含有姜黄素和不含姜黄素的配方的凝胶硬度时,发现随着姜黄素的增溶,硬度显著降低。与添加氯化钠相比,添加氯化钾可防止含有 CUR 的凝胶硬度下降。总之,添加金属盐对 MAG 的胶束和凝胶形成有显著影响。尤其是在制备凝胶溶解的 CUR 时,添加 KCl 更为有效。
{"title":"The Impact of Adding a Cationic Metal Salt and Curcumin to Monoammonium Glycyrrhizic Acid on Its Solubilizing Capacity and Gelation.","authors":"Kenta Ando, Hiromasa Uchiyama, Katsuhiko Minoura, Kazunori Kadota, Yuichi Tozuka","doi":"10.1248/cpb.c24-00399","DOIUrl":"https://doi.org/10.1248/cpb.c24-00399","url":null,"abstract":"<p><p>Monoammonium glycyrrhizic acid (MAG), a glycyrrhizic acid monoammonium salt, is a naturally derived low-molecular-weight gelling agent with surface-active properties. It has the capacity to individually facilitate the preparation of gel-solubilized drugs. As MAG is an anionic surfactant with carboxyl groups, the addition of counterions may affect micelle formation and gelation. In this study, the solubilization and gelling properties of MAG were investigated following the addition of metal salts (NaCl and KCl). The addition of metal salts resulted in a decrease in the critical micelle concentration and an increase in gel hardness. Supersaturation of curcumin (CUR) was maintained by the addition of metal salts because of increased micelle number and viscosity. When the gel hardness was compared between formulations with and without CUR, a significant reduction in hardness was observed with the solubilization of CUR. The addition of KCl prevented the decrease in the hardness of gels containing CUR compared to the addition of NaCl. Put together, the addition of metal salts had a noteworthy impact on micelle and gel formation of MAG. In particular, the addition of KCl was more effective in the preparation of gel-solubilized CUR.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aya Kuwata, Tetsuo Ono, Yuri Tsuchiya, Etsuo Yonemochi
In order to create and offer superior pharmaceuticals for consumers who wish to be relieved of headache and fever as soon as possible, we established HYDROFLASH manufacturing method that enables us to offer fast disintegration tablets containing loxoprofen sodium (LX), which are difficult to disintegrate. As a result of screening excipients, tablets using mannitol showed the fastest disintegration time, about 2 min. From the result of viscosity measurement, we found that LX produced higher viscosity when dissolved in water. This suggests that tablets containing LX disintegrate slower by inhibiting the penetration of water into the tablet due to the viscosity caused of LX. Therefore, we created a manufacturing method to make it easy for water to penetrate the tablet. It is possible to achieve fastest disintegration in about 30 s for tablets containing LX by granulating in a fluidized-bed with spraying of the dispersion of light anhydrous silicic acid (LASA). LX-containing tablets manufactured by the HYDROFLASH method disintegrated immediately after contact with water. Furthermore, it was observed that LASA was uniformly dotted on the surface of tablets by HYDROFLASH method, compared with other manufacturing methods. We considered that by fluidized-bed granulation with LASA dispersion (HYDROFLASH manufacturing method), water permeates through LASA on the tablet surface regardless of viscosity of LX. Futhermore, LX-containing tablets by the HYDROFLASH method showed that the dissolution rate of LX was nearly 100% at 5 min after starting the test. We considered that the initial dissolution became faster because of the fast disintegration.