Takashi Kamei, Jun Miyazaki, Ryoga Hori, Hiroaki Saito, Tatsuo Takahashi, Ken-Ichi Shinohara, Masakazu Miura, Hirokazu Suzuki
Butin and butein are significant bioactive flavanones derived from plants, existing as tautomers of each other. However, their physicochemical attributes, such as their spectral profiles under varying experimental conditions in aqueous solutions and established chromatographic methods for distinguishing between them, remain undetermined. In this study, we determined the basic properties of butin and butein using conventional spectroscopic, reversed-phase, and chiral HPLC analyses. The spectra of the synthesized butin and butein were analyzed using a UV-Vis spectrophotometer in several solvents with different polarities as well as in aqueous solutions at various pH values. Furthermore, the behavior of the measured spectra was reproduced by calculations to reveal the effects of the solvent and pH on the spectra of butin and butein in organic and aqueous solutions. Subsequently, we assessed the structural stability of butin and butein using reversed-phase HPLC, which revealed that butein is unstable compared with butin in a general culture medium. The synthesized butin was effectively separated into R- and S-isomers with positive and negative Cotton effects, respectively, via HPLC using a chiral column. These findings will aid in uncovering the individual properties of both butin and butein that may have been concealed by their tautomerism and enable the synthesis of S-butin, which is typically challenging and time-consuming to isolate.
{"title":"Spectral and HPLC Analyses of Synthesized Butin and Butein.","authors":"Takashi Kamei, Jun Miyazaki, Ryoga Hori, Hiroaki Saito, Tatsuo Takahashi, Ken-Ichi Shinohara, Masakazu Miura, Hirokazu Suzuki","doi":"10.1248/cpb.c24-00239","DOIUrl":"https://doi.org/10.1248/cpb.c24-00239","url":null,"abstract":"<p><p>Butin and butein are significant bioactive flavanones derived from plants, existing as tautomers of each other. However, their physicochemical attributes, such as their spectral profiles under varying experimental conditions in aqueous solutions and established chromatographic methods for distinguishing between them, remain undetermined. In this study, we determined the basic properties of butin and butein using conventional spectroscopic, reversed-phase, and chiral HPLC analyses. The spectra of the synthesized butin and butein were analyzed using a UV-Vis spectrophotometer in several solvents with different polarities as well as in aqueous solutions at various pH values. Furthermore, the behavior of the measured spectra was reproduced by calculations to reveal the effects of the solvent and pH on the spectra of butin and butein in organic and aqueous solutions. Subsequently, we assessed the structural stability of butin and butein using reversed-phase HPLC, which revealed that butein is unstable compared with butin in a general culture medium. The synthesized butin was effectively separated into R- and S-isomers with positive and negative Cotton effects, respectively, via HPLC using a chiral column. These findings will aid in uncovering the individual properties of both butin and butein that may have been concealed by their tautomerism and enable the synthesis of S-butin, which is typically challenging and time-consuming to isolate.</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":"141554227","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}
Alzheimer's disease (AD) is a common form of dementia. Although the causal mechanisms of AD are not fully understood, intracerebral accumulation of amyloid beta (Aβ) and tau aggregates seems to play an important role in disease development. Therefore, numerous experimental and clinical studies targeting the Aβ and tau proteins have been performed. However, these treatments have not achieved good clinical results. Additionally, recent findings have indicated that immune abnormalities contribute to the pathogenesis of AD. Several immune- and microglia-related genes have been identified as putative causative genes for the disease. Microglia, which are resident immune cells in the central nervous system (CNS), are key players that maintain brain homeostasis by communicating with other cells, such as astrocytes and immune cells, in or around the CNS. Furthermore, dysfunction of microglia and the immune system of the CNS could lead to chronic neuroinflammation and impairment of protective neuroimmune responses, which have been associated with the pathogenesis of AD and other forms of dementia. In this review, we assemble information regarding genetic evidence, imaging and biofluid biomarkers, and the pathophysiology of AD, especially highlighting bilateral (protective or detrimental) microglial functions, thus connecting neuroimmune dysfunction and AD. We also introduce candidate drugs to target neuroimmune dysfunction in AD. Finally, we discuss future therapeutic precision medicine approaches for AD, which could be achieved by identifying and targeting signals critical for AD pathogenesis through analyses of interactions between genetic risk factors, as well as identifying and modulating disease-relevant immune cell populations.
阿尔茨海默病(AD)是一种常见的痴呆症。虽然阿尔茨海默病的致病机制尚未完全明了,但淀粉样蛋白β(Aβ)和tau聚集体在脑内的积聚似乎在疾病的发展中起着重要作用。因此,针对 Aβ 和 tau 蛋白的实验和临床研究层出不穷。然而,这些治疗方法并未取得良好的临床效果。此外,最近的研究结果表明,免疫异常也是AD的发病机制之一。一些与免疫和小胶质细胞相关的基因已被确定为该疾病的潜在致病基因。小胶质细胞是中枢神经系统(CNS)中的常驻免疫细胞,是通过与中枢神经系统内或周围的其他细胞(如星形胶质细胞和免疫细胞)交流来维持大脑平衡的关键角色。此外,小胶质细胞和中枢神经系统免疫系统的功能障碍可能会导致慢性神经炎症和保护性神经免疫反应的损害,这与注意力缺失症和其他形式痴呆症的发病机制有关。在这篇综述中,我们汇集了有关遗传学证据、成像和生物流体生物标志物以及 AD 病理生理学的信息,特别强调了小胶质细胞的双边(保护性或有害性)功能,从而将神经免疫功能障碍与 AD 联系起来。我们还介绍了针对 AD 神经免疫功能障碍的候选药物。最后,我们讨论了未来的 AD 精准医学治疗方法,这些方法可以通过分析遗传风险因素之间的相互作用来识别和靶向对 AD 发病至关重要的信号,以及识别和调节与疾病相关的免疫细胞群来实现。
{"title":"Neuroimmune Dysfunction in Alzheimer's Disease and Other Forms of Dementia.","authors":"Takuya Yamane, Takeshi Yoshioka, Yusuke Shimo","doi":"10.1248/cpb.c23-00464","DOIUrl":"https://doi.org/10.1248/cpb.c23-00464","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a common form of dementia. Although the causal mechanisms of AD are not fully understood, intracerebral accumulation of amyloid beta (Aβ) and tau aggregates seems to play an important role in disease development. Therefore, numerous experimental and clinical studies targeting the Aβ and tau proteins have been performed. However, these treatments have not achieved good clinical results. Additionally, recent findings have indicated that immune abnormalities contribute to the pathogenesis of AD. Several immune- and microglia-related genes have been identified as putative causative genes for the disease. Microglia, which are resident immune cells in the central nervous system (CNS), are key players that maintain brain homeostasis by communicating with other cells, such as astrocytes and immune cells, in or around the CNS. Furthermore, dysfunction of microglia and the immune system of the CNS could lead to chronic neuroinflammation and impairment of protective neuroimmune responses, which have been associated with the pathogenesis of AD and other forms of dementia. In this review, we assemble information regarding genetic evidence, imaging and biofluid biomarkers, and the pathophysiology of AD, especially highlighting bilateral (protective or detrimental) microglial functions, thus connecting neuroimmune dysfunction and AD. We also introduce candidate drugs to target neuroimmune dysfunction in AD. Finally, we discuss future therapeutic precision medicine approaches for AD, which could be achieved by identifying and targeting signals critical for AD pathogenesis through analyses of interactions between genetic risk factors, as well as identifying and modulating disease-relevant immune cell populations.</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":"141466476","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}
Alzheimer's disease (AD) is the leading cause of senile dementia, and the rapid increase in the frequency of AD cases has been attributed to population aging. However, current drugs have difficulty adequately suppressing symptoms and there is still a medical need for symptomatic agents. On the other hand, it has recently become clear that epigenetic dysfunctions are deeply involved in the development of cognitive impairments. Therefore, epigenetics-related proteins have attracted much attention as drug targets for AD. Early-developed epigenetic inhibitors were inappropriate for AD treatment because of their limited potential for oral administration, blood-brain barrier penetration, high target selectivity, and sufficient dose-limiting toxicity which are essential properties for small molecule drugs targeting chronic neurodegenerative diseases such as AD. In recent years, drug discovery studies have been actively performed to overcome such problems and several novel inhibitors targeting the epigenetics-related proteins are of interest as promising AD therapeutic agents. Here, we review the small molecule inhibitors of histone deacetylase (HDAC), lysine-specific demethylase 1 (LSD1) or bromodomains and extra-terminal domain (BET) protein, that enable memory function improvement in AD model mice.
{"title":"Epigenetic Inhibitors as Alzheimer's Disease Therapeutic Agents.","authors":"Yasunobu Yamashita, Yukihiro Itoh, Yuri Takada, Takayoshi Suzuki","doi":"10.1248/cpb.c23-00027","DOIUrl":"https://doi.org/10.1248/cpb.c23-00027","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of senile dementia, and the rapid increase in the frequency of AD cases has been attributed to population aging. However, current drugs have difficulty adequately suppressing symptoms and there is still a medical need for symptomatic agents. On the other hand, it has recently become clear that epigenetic dysfunctions are deeply involved in the development of cognitive impairments. Therefore, epigenetics-related proteins have attracted much attention as drug targets for AD. Early-developed epigenetic inhibitors were inappropriate for AD treatment because of their limited potential for oral administration, blood-brain barrier penetration, high target selectivity, and sufficient dose-limiting toxicity which are essential properties for small molecule drugs targeting chronic neurodegenerative diseases such as AD. In recent years, drug discovery studies have been actively performed to overcome such problems and several novel inhibitors targeting the epigenetics-related proteins are of interest as promising AD therapeutic agents. Here, we review the small molecule inhibitors of histone deacetylase (HDAC), lysine-specific demethylase 1 (LSD1) or bromodomains and extra-terminal domain (BET) protein, that enable memory function improvement in AD model mice.</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":"141466473","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}
The current study aimed to explore the impact of buffer species on the dissolution behavior of orally disintegrating tablets (ODT) containing a basic polymer and its influence on bioequivalence (BE) prediction. Fexofenadine hydrochloride ODT formulations were used as the model formulations, Allegra® as the reference formulation, and generic formulations A and B as the test formulations. Allegra®, generic A, and generic B are ODT formulations that contain aminoalkyl methacrylate copolymers E (Eudragit® E, EUD-E), a basic polymer commonly used to mask the bitter taste of drugs. Both generic A and generic B have been known to be bioequivalent to Allegra®. The dissolution tests were conducted using a compendial paddle, with either bicarbonate (10 mM, pH 6.8) or phosphate buffer (25 mM, pH 6.8) as the dissolution media. A floating lid was employed to cover the surface of the bicarbonate buffer to prevent volatilization. Results indicated that in phosphate buffer, the dissolution profiles of Allegra and generic B significantly varied from that of generic A, whereas in the bicarbonate buffer, the dissolution profiles of Allegra, generic A, and generic B were comparable. These findings suggest that the use of bicarbonate buffer may offer a more precise prediction of human bioequivalence compared to phosphate buffer.
本研究旨在探讨缓冲剂种类对含碱性聚合物的口腔崩解片(ODT)溶出行为的影响及其对生物等效性(BE)预测的影响。盐酸非索非那定口腔崩解片制剂作为模型制剂,Allegra®作为参比制剂,普通制剂A和B作为试验制剂。Allegra®、普通制剂 A 和普通制剂 B 都是含有甲基丙烯酸氨基烷基共聚物 E(Eudragit® E,EUD-E)的 ODT 制剂,EUD-E 是一种碱性聚合物,常用来掩盖药物的苦味。据了解,仿制药 A 和仿制药 B 与 Allegra® 具有生物等效性。溶解试验使用药典桨进行,溶解介质为碳酸氢盐(10 mM,pH 6.8)或磷酸盐缓冲液(25 mM,pH 6.8)。使用浮盖覆盖碳酸氢盐缓冲液表面以防止挥发。结果表明,在磷酸盐缓冲液中,阿莱格拉和非专利药 B 的溶出曲线与非专利药 A 的溶出曲线差异很大,而在碳酸氢盐缓冲液中,阿莱格拉、非专利药 A 和非专利药 B 的溶出曲线相当。这些发现表明,与磷酸盐缓冲液相比,使用碳酸氢盐缓冲液可以更精确地预测人体生物等效性。
{"title":"Dissolution Profiles of Oral Disintegrating Tablet with Taste Masking Granule Polymer Coating in Biorelevant Bicarbonate Buffer.","authors":"Masaki Higashino, Kiyohiko Sugano","doi":"10.1248/cpb.c23-00783","DOIUrl":"10.1248/cpb.c23-00783","url":null,"abstract":"<p><p>The current study aimed to explore the impact of buffer species on the dissolution behavior of orally disintegrating tablets (ODT) containing a basic polymer and its influence on bioequivalence (BE) prediction. Fexofenadine hydrochloride ODT formulations were used as the model formulations, Allegra<sup>®</sup> as the reference formulation, and generic formulations A and B as the test formulations. Allegra<sup>®</sup>, generic A, and generic B are ODT formulations that contain aminoalkyl methacrylate copolymers E (Eudragit<sup>®</sup> E, EUD-E), a basic polymer commonly used to mask the bitter taste of drugs. Both generic A and generic B have been known to be bioequivalent to Allegra<sup>®</sup>. The dissolution tests were conducted using a compendial paddle, with either bicarbonate (10 mM, pH 6.8) or phosphate buffer (25 mM, pH 6.8) as the dissolution media. A floating lid was employed to cover the surface of the bicarbonate buffer to prevent volatilization. Results indicated that in phosphate buffer, the dissolution profiles of Allegra and generic B significantly varied from that of generic A, whereas in the bicarbonate buffer, the dissolution profiles of Allegra, generic A, and generic B were comparable. These findings suggest that the use of bicarbonate buffer may offer a more precise prediction of human bioequivalence compared to phosphate buffer.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118918","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}
A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the β-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.
一种 12-酮型齐墩果酸衍生物(4)已被确认为一种强效的抗人类免疫缺陷病毒 1 型(HIV-1)化合物,可与多种类型的 HIV-1 中和抗体产生协同效应。在本研究中,我们利用一种常见的关键合成中间体,以 12-酮型齐墩果酸衍生物的化学结构为基础,对一种抗 HIV 化合物进行了后期衍生化。为了实施这一策略,我们设计了一种二酮型齐墩果酸衍生物(5)进行化学选择性转化,以他汀单元上的羧基和羟基以及齐墩果酸单元上的 3-羰基作为正交合成手柄。我们进行了四种化学选择性转化,最终确定吲哚型衍生物 (16) 为新型强效抗 HIV 化合物。此外,我们还进一步优化了他汀单元上的β-羟基,得到了 R-4-异丁基γ-氨基酸型衍生物 (6),该衍生物具有与 4 相似的强效抗 HIV 活性,但细胞毒性较低。
{"title":"Late-Stage Derivatization of Oleanolic Acid-Based Anti-HIV-1 Compounds.","authors":"Reon Takeuchi, Junko Fujimoto, Yoshinori Taguchi, Ryuji Ide, Ryuji Kyan, Kohei Sato, Nobuyuki Mase, Masaru Yokoyama, Shigeyoshi Harada, Tetsuo Narumi","doi":"10.1248/cpb.c23-00891","DOIUrl":"10.1248/cpb.c23-00891","url":null,"abstract":"<p><p>A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the β-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140206350","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}
Takashi Hasegawa, Kenji Tsukigawa, Kindness Commey, Mina Sakuragi, Shuhei Imoto, Kazuaki Taguchi, Koji Nishi, Masaki Otagiri, Keishi Yamasaki
Pirarubicin (THP) shows more rapid intracellular uptake, more effective antitumor activity, and less cardiac toxicity, compared to doxorubicin. However, THP is distributed to both tumor and normal tissues indiscriminately. This study aimed to develop a nanosuspension to deliver THP to tumor tissues more efficiently. Fatty-acid-modified THPs (FA-THPs; octanoic acid, dodecanoic acid, palmitic acid-THPs) were synthesized to increase the hydrophobicity of THP. Nanosuspensions of these FA-THPs were then prepared using an antisolvent precipitation technique. Among the FA-THPs, the most efficiently drug-loaded nanosuspension was obtained from palmitic acid-THP (pal-THP) using an aqueous antisolvent containing bovine serum albumin as a stabilizer. The pal-THP nanoparticles in the nanosuspension were confirmed to be of optimal size (100–125 nm) for delivery to tumor tissues using dynamic light scattering and transmission electron microscopy. The pal-THP nanosuspension showed cytotoxicity in colon 26 cells. The nanosuspension was shown to disintegrate in the presence of surfactants such as lecithin, liberating pal-THP, which was converted to free THP in acidic media. It is therefore proposed that pal-THP nanoparticles that reach tumor cells after intravenous administration would exert antitumor effect by liberating pal-THP (i.e., disintegration of nanoparticles by the interaction with cell membrane), followed by the release of free THP in the acidic milieu of tumor cells. These findings indicate that FA-THP nanosuspensions, particularly pal-THP nanosuspension, hold promise as a candidate for cancer treatment. However, further in vivo studies are necessary.