Yilei Huang, Han Zhang, Xinyan Peng, Qingwei Zhang
The mitochondrial pyruvate carrier (MPC) exists in the mitochondria inner membrane which transports pyruvate to the mitochondrial matrix. Evidence shows that MPC is the breakthrough point to study the regulation of basic energy metabolism, the dysfunction of which may lead to metabolic disturbance. Due to its important metabolic function, MPC has been considered a potential therapeutic target for diabetes, alopecia, cancers, neurodegenerative diseases, and liver metabolic diseases. However, MPC' protein crystal structure is still not clear as the proteins involved were only identified 10 years ago, making it difficult to carry out rational drug design based on receptor structure. In this review, we summarize the latest applications of MPC in different diseases and discuss the recent advances in pharmacochemical strategies of small-molecule inhibitors of MPC, hoping to promote the development of specific MPC inhibitors.
{"title":"Recent Advances in Mitochondrial Pyruvate Carrier Inhibitors","authors":"Yilei Huang, Han Zhang, Xinyan Peng, Qingwei Zhang","doi":"10.1055/s-0044-1788072","DOIUrl":"https://doi.org/10.1055/s-0044-1788072","url":null,"abstract":"The mitochondrial pyruvate carrier (MPC) exists in the mitochondria inner membrane which transports pyruvate to the mitochondrial matrix. Evidence shows that MPC is the breakthrough point to study the regulation of basic energy metabolism, the dysfunction of which may lead to metabolic disturbance. Due to its important metabolic function, MPC has been considered a potential therapeutic target for diabetes, alopecia, cancers, neurodegenerative diseases, and liver metabolic diseases. However, MPC' protein crystal structure is still not clear as the proteins involved were only identified 10 years ago, making it difficult to carry out rational drug design based on receptor structure. In this review, we summarize the latest applications of MPC in different diseases and discuss the recent advances in pharmacochemical strategies of small-molecule inhibitors of MPC, hoping to promote the development of specific MPC inhibitors.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"16 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141646559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Necroptosis, a caspase-independent regulated cell death, is primarily mediated by the serine/threonine kinases RIPK1 and RIPK3, and the mixed lineage kinase domain-like protein (MLKL). Targeting necroptosis is a validated therapeutic strategy for various diseases. We screened compound 1, a novel benzimidazole-based necroptosis inhibitor, from our in-house compound library. We assessed its inhibitory roles and mechanisms in blocking HT-29 cell necroptosis. HT-29 cells were treated with pan caspase inhibitor Z-VAD-FMK + Smac mimetic (TSZ), or Z-VAD-FMK + cycloheximide (TCZ), then with tumor necrosis factor α (TNFα) to induce necroptosis in vitro. Prior to stimulation, cells were exposed to compound 1. GSK'843 served as a control drug. HT-29 cells were treated with TNFα + Smac mimetic (TS) or TNFα + cycloheximide (TC) to induce apoptosis in vitro. Cell viability, cell death, and necroptotic cells were evaluated by luminescence-based CellTiter-Lumi assay or flow cytometry. Western blots, immunoprecipitation, and KINOMEscan technology were used to assess RIPK1, RIPK3, and MLKL's involvement in compound 1's mechanisms. Compound 1's roles in mouse TNFα induced systemic inflammatory response syndrome (SIRS) in mice were also investigated by assessing body temperature, mouse survival rate, and interleukin (IL)-β and IL-6 levels in respective tissues. We found that necroptosis triggered by TSZ or TCZ was effectively mitigated by compound 1, showing a dose-responsive inhibition, and it could protect mice from TNF-induced SIRS. The mechanism study showed that compound 1 could interact with RIPK1, inhibiting RIPK1 phosphorylation activation to block necrosome formation in necroptotic cells. In summary, compound 1 is a promising lead compound for developing treatments targeting diseases associated with necroptosis.
{"title":"Discovery of a Novel Benzimidazole Necroptosis Inhibitor from an In-House Compound Library","authors":"Yu Zou, Yue Chai, Hong-Li Shao, Shuyu Wang, Ruilin Hou, Runhui Liu, Linjing Zhao, Chunlin Zhuang","doi":"10.1055/s-0044-1788077","DOIUrl":"https://doi.org/10.1055/s-0044-1788077","url":null,"abstract":"Necroptosis, a caspase-independent regulated cell death, is primarily mediated by the serine/threonine kinases RIPK1 and RIPK3, and the mixed lineage kinase domain-like protein (MLKL). Targeting necroptosis is a validated therapeutic strategy for various diseases. We screened compound 1, a novel benzimidazole-based necroptosis inhibitor, from our in-house compound library. We assessed its inhibitory roles and mechanisms in blocking HT-29 cell necroptosis. HT-29 cells were treated with pan caspase inhibitor Z-VAD-FMK + Smac mimetic (TSZ), or Z-VAD-FMK + cycloheximide (TCZ), then with tumor necrosis factor α (TNFα) to induce necroptosis in vitro. Prior to stimulation, cells were exposed to compound 1. GSK'843 served as a control drug. HT-29 cells were treated with TNFα + Smac mimetic (TS) or TNFα + cycloheximide (TC) to induce apoptosis in vitro. Cell viability, cell death, and necroptotic cells were evaluated by luminescence-based CellTiter-Lumi assay or flow cytometry. Western blots, immunoprecipitation, and KINOMEscan technology were used to assess RIPK1, RIPK3, and MLKL's involvement in compound 1's mechanisms. Compound 1's roles in mouse TNFα induced systemic inflammatory response syndrome (SIRS) in mice were also investigated by assessing body temperature, mouse survival rate, and interleukin (IL)-β and IL-6 levels in respective tissues. We found that necroptosis triggered by TSZ or TCZ was effectively mitigated by compound 1, showing a dose-responsive inhibition, and it could protect mice from TNF-induced SIRS. The mechanism study showed that compound 1 could interact with RIPK1, inhibiting RIPK1 phosphorylation activation to block necrosome formation in necroptotic cells. In summary, compound 1 is a promising lead compound for developing treatments targeting diseases associated with necroptosis.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"109 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141647403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jie Liu, Qinghui Fu, Qin Li, Yani Yang, Yue Zhang, Kaili Yang, Guohao Sun, Jiayu Luo, Weigen Lu, Jun He
Microfluidic technology facilitates precise control over fluid mixing and interactions between the components, including self-assembly and precipitation. It offers new options for accurately manufacturing particles and holds significant potential in advancing micro/nanoparticle drug delivery systems (DDSs). Various microchannel/microfluidic chips have been explored to construct micro/nanoparticle DDSs. The precise manipulation of particle size, morphology, structure, stiffness, surface characteristics, and elasticity through microfluidic technology relies on specific microchannel geometrical designs and the application of exogenous energy, adhering to the principles of fluid motion. Consequently, this enables reproducible control over critical quality attributes (CQAs), such as particle size and distribution, encapsulation efficiency, drug loading, in vitro and in vivo drug delivery profiles, Zeta potential, and targeting capabilities, for micro/nanoparticle DDSs. In this review, we categorize microfluidic techniques and explore recent research developments in novel microchannel structures spanning the past 5 years (2018–2023) and their applications in micro/nanoparticle DDSs. Additionally, we elucidate the latest manipulation strategies of microfluidic techniques that impact foundational structures related to the CQAs of micro/nanoparticle DDSs. Furthermore, we offer insights into the industrial applications and challenges microfluidic techniques face in the context of novel micro/nanoparticle DDSs.
{"title":"Research Strategies for Precise Manipulation of Micro/Nanoparticle Drug Delivery Systems Using Microfluidic Technology: A Review","authors":"Jie Liu, Qinghui Fu, Qin Li, Yani Yang, Yue Zhang, Kaili Yang, Guohao Sun, Jiayu Luo, Weigen Lu, Jun He","doi":"10.1055/s-0044-1786180","DOIUrl":"https://doi.org/10.1055/s-0044-1786180","url":null,"abstract":"Microfluidic technology facilitates precise control over fluid mixing and interactions between the components, including self-assembly and precipitation. It offers new options for accurately manufacturing particles and holds significant potential in advancing micro/nanoparticle drug delivery systems (DDSs). Various microchannel/microfluidic chips have been explored to construct micro/nanoparticle DDSs. The precise manipulation of particle size, morphology, structure, stiffness, surface characteristics, and elasticity through microfluidic technology relies on specific microchannel geometrical designs and the application of exogenous energy, adhering to the principles of fluid motion. Consequently, this enables reproducible control over critical quality attributes (CQAs), such as particle size and distribution, encapsulation efficiency, drug loading, in vitro and in vivo drug delivery profiles, Zeta potential, and targeting capabilities, for micro/nanoparticle DDSs. In this review, we categorize microfluidic techniques and explore recent research developments in novel microchannel structures spanning the past 5 years (2018–2023) and their applications in micro/nanoparticle DDSs. Additionally, we elucidate the latest manipulation strategies of microfluidic techniques that impact foundational structures related to the CQAs of micro/nanoparticle DDSs. Furthermore, we offer insights into the industrial applications and challenges microfluidic techniques face in the context of novel micro/nanoparticle DDSs.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"91 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141105905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer is one of the most fatal diseases that attract numerous efforts and attention from researchers. Among plentiful therapeutic agents, chemotherapy is frequently used in treating virulent tumors, and its insistent administration is useful in the ablation of cancers; however, it also produces side effects. Biomimetic drug delivery systems (BDDSs) provide an alternative route for antitumor therapy. Their endogenous substances may be extracellular vesicles, living cells, cell membranes, etc., which optimize single-agent chemotherapy. They “upgrade” traditional drug delivery platforms by combining the original drug with itself, disguised as a Trojan Horse, to trick the immune system or tumor tissues to achieve higher targeting and lower immunogenicity. Herein, we review three BDDS strategies being used recently in antitumor drug development and their advances, aiming at providing general guidelines and opportunities in this field in the future.
{"title":"Advances in Tumor Targeting Biomimetic Drug Delivery Systems: A Promising Approach for Antitumor Therapy","authors":"Ziyi Mo, Jiao He, Man Li, Rong Guo, Qin He","doi":"10.1055/s-0044-1786681","DOIUrl":"https://doi.org/10.1055/s-0044-1786681","url":null,"abstract":"Cancer is one of the most fatal diseases that attract numerous efforts and attention from researchers. Among plentiful therapeutic agents, chemotherapy is frequently used in treating virulent tumors, and its insistent administration is useful in the ablation of cancers; however, it also produces side effects. Biomimetic drug delivery systems (BDDSs) provide an alternative route for antitumor therapy. Their endogenous substances may be extracellular vesicles, living cells, cell membranes, etc., which optimize single-agent chemotherapy. They “upgrade” traditional drug delivery platforms by combining the original drug with itself, disguised as a Trojan Horse, to trick the immune system or tumor tissues to achieve higher targeting and lower immunogenicity. Herein, we review three BDDS strategies being used recently in antitumor drug development and their advances, aiming at providing general guidelines and opportunities in this field in the future.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141110938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"3D Printing Pharmaceuticals: Current Status and Future Opportunities","authors":"Senping Cheng, Timothy S. Tracy, Xiaoling Li","doi":"10.1055/s-0044-1782512","DOIUrl":"https://doi.org/10.1055/s-0044-1782512","url":null,"abstract":"","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"11 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nitidine chloride (NC) is a natural product that promotes the expression of interleukin-10 (IL-10) in macrophages by inhibiting topoisomerase I (TopoI) under stimulation by lipopolysaccharides (LPSs) and can be used in the treatment of sepsis. However, NC's poor water solubility limits its applications. This study aimed to design and synthesize a series of derivatives by simplifying the A- and E-rings in the structure of NC and introducing oxygen-containing groups, using NC as the lead compound. In this work, the ability of NC and its derivatives to induce IL-10 secretion and inhibit TopoI was evaluated. The water solubility of the compounds was determined in phosphate-buffered saline. An LPS-induced sepsis in mice was prepared to assess the activity of the compounds in vivo. Our data suggested that compound 6F showed better activity in inducing IL-10 secretion and inhibiting TopoI, and its water solubility was at least 500-fold higher than that of NC. When septic mice were given 6F (3 mg/kg), their survival rate was comparable to those treated with NC. Based on our findings, 6F may be a new drug candidate for the treatment of sepsis.
{"title":"Discovery of Topoisomerase I Inhibitor Nitidine Derivatives with IL-10 Enhancing Activity for the Treatment of Sepsis","authors":"Siyu Liu, Yanting Pang, Zeng Zhao, Qingyan Sun","doi":"10.1055/s-0044-1780496","DOIUrl":"https://doi.org/10.1055/s-0044-1780496","url":null,"abstract":"Nitidine chloride (NC) is a natural product that promotes the expression of interleukin-10 (IL-10) in macrophages by inhibiting topoisomerase I (TopoI) under stimulation by lipopolysaccharides (LPSs) and can be used in the treatment of sepsis. However, NC's poor water solubility limits its applications. This study aimed to design and synthesize a series of derivatives by simplifying the A- and E-rings in the structure of NC and introducing oxygen-containing groups, using NC as the lead compound. In this work, the ability of NC and its derivatives to induce IL-10 secretion and inhibit TopoI was evaluated. The water solubility of the compounds was determined in phosphate-buffered saline. An LPS-induced sepsis in mice was prepared to assess the activity of the compounds in vivo. Our data suggested that compound 6F showed better activity in inducing IL-10 secretion and inhibiting TopoI, and its water solubility was at least 500-fold higher than that of NC. When septic mice were given 6F (3 mg/kg), their survival rate was comparable to those treated with NC. Based on our findings, 6F may be a new drug candidate for the treatment of sepsis.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"13 69","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140260570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To date, more than 150 chemical modifications have been disclosed in different RNA species, which are employed to diversify the structure and function of RNA in living organisms. The N 6-methyladenosine (m6A) modification, which is found in the adenosine N 6 site of RNA, has been demonstrated to be the most heavy modification in the mRNA in cells. Moreover, the m6A modification in mRNAs of mammalian and other eukaryotic cells is highly conserved and mandatorily encoded. Increasing evidence indicates that the m6A modification plays a pivotal role in gene-expression regulation and cell-fate decisions. Here, we summarize the most recent m6A-sequencing technology, as well as the molecular mechanism underlying its occurrence, development, and potential use as a target for the treatment of human diseases. Furthermore, our review highlights other newly discovered chemical modifications of RNA that are associated with human disease, as well as their underlying molecular mechanisms. Thus, significant advancements have been made in qualitative/quantitative m6A detection and high-throughput sequencing, and research linking this RNA modification to disease. Efforts toward simplified and more accessible chemical/biological technologies that contribute to precision medicine are ongoing, to benefit society and patients alike.
{"title":"Sequencing, Physiological Regulation, and Representative Disease Research Progress of RNA m6A Modification","authors":"Xiaoqian Chen, Yuanyuan Li, Youfang Gan, Yuyang Guo, Hongling Zhou, Rui Wang","doi":"10.1055/s-0044-1780506","DOIUrl":"https://doi.org/10.1055/s-0044-1780506","url":null,"abstract":"To date, more than 150 chemical modifications have been disclosed in different RNA species, which are employed to diversify the structure and function of RNA in living organisms. The N\u0000 6-methyladenosine (m6A) modification, which is found in the adenosine N\u0000 6 site of RNA, has been demonstrated to be the most heavy modification in the mRNA in cells. Moreover, the m6A modification in mRNAs of mammalian and other eukaryotic cells is highly conserved and mandatorily encoded. Increasing evidence indicates that the m6A modification plays a pivotal role in gene-expression regulation and cell-fate decisions. Here, we summarize the most recent m6A-sequencing technology, as well as the molecular mechanism underlying its occurrence, development, and potential use as a target for the treatment of human diseases. Furthermore, our review highlights other newly discovered chemical modifications of RNA that are associated with human disease, as well as their underlying molecular mechanisms. Thus, significant advancements have been made in qualitative/quantitative m6A detection and high-throughput sequencing, and research linking this RNA modification to disease. Efforts toward simplified and more accessible chemical/biological technologies that contribute to precision medicine are ongoing, to benefit society and patients alike.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"16 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140268718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhonghua Luo, Guodong Sun, Guowei Wang, Xin Zhang, Yang Zhang, Ji Zhang
Rimegepant is a calcitonin gene-related peptide antagonist used for acute treatment and prevention of migraine. We herein attempt to explore an efficient and practiced method for scale-up, regio- and enantioselective synthesis of (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1), a key intermediate of rimegepant. In this work, a Ru-catalyzed asymmetric transfer hydrogenation (ATH) reaction was a key step. The optimization of the reaction conditions involved exploring the reaction parameters including catalysts, bases, and solvents. The results suggested that the Ru-catalyzed ATH process using formic acid as the hydrogen donor could be operated under mild conditions at a low catalyst loading (0.5 mol%), affording a high yield (92.1% yield with 99.8% purity) and gratifying enantioselectivity (99.9% ee) of the target product (1). This work first reported the Ru-catalyzed ATH process in the synthesis of key intermediates of rimegepant. The optimized ATH process was easy to implement and cost-effective, making it particularly suitable for manufacturing scale production.
Rimegepant 是一种降钙素基因相关肽拮抗剂，用于偏头痛的急性治疗和预防。我们在此尝试探索一种高效、实用的方法，用于放大、区域和对映体选择性合成 (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1)，它是 Rimegepant 的一种关键中间体。在这项工作中，Ru 催化的不对称转移加氢（ATH）反应是一个关键步骤。反应条件的优化包括对催化剂、碱和溶剂等反应参数的探索。结果表明，以甲酸为氢供体的 Ru 催化 ATH 反应可在温和条件下以较低的催化剂负载量（0.5 摩尔%）进行操作，从而获得高产率（92.1% 收率，99.8% 纯度）和令人满意的目标产物对映体选择性（99.9% ee）(1)。该研究首次报道了 Ru 催化 ATH 工艺合成利美喷司关键中间体的过程。优化后的 ATH 工艺易于实现且具有成本效益，因此特别适用于大规模生产。
{"title":"Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist","authors":"Zhonghua Luo, Guodong Sun, Guowei Wang, Xin Zhang, Yang Zhang, Ji Zhang","doi":"10.1055/s-0044-1780495","DOIUrl":"https://doi.org/10.1055/s-0044-1780495","url":null,"abstract":"Rimegepant is a calcitonin gene-related peptide antagonist used for acute treatment and prevention of migraine. We herein attempt to explore an efficient and practiced method for scale-up, regio- and enantioselective synthesis of (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1), a key intermediate of rimegepant. In this work, a Ru-catalyzed asymmetric transfer hydrogenation (ATH) reaction was a key step. The optimization of the reaction conditions involved exploring the reaction parameters including catalysts, bases, and solvents. The results suggested that the Ru-catalyzed ATH process using formic acid as the hydrogen donor could be operated under mild conditions at a low catalyst loading (0.5 mol%), affording a high yield (92.1% yield with 99.8% purity) and gratifying enantioselectivity (99.9% ee) of the target product (1). This work first reported the Ru-catalyzed ATH process in the synthesis of key intermediates of rimegepant. The optimized ATH process was easy to implement and cost-effective, making it particularly suitable for manufacturing scale production.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140281007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The organosulfur frameworks containing C–S bonds are important structural motifs in various biologically active molecules and functional materials. In this regard, transition-metal catalysis using chemical oxidants to prime reactions has emerged as the most common method, however, is prone to several side reactions such as dimerization and overoxidation. In recent years, organic electrosynthesis has become a hot topic due to its eco-friendly and mild process in which costly catalysts and toxic oxidants could be replaced by electrons. This perspective summarized the recently developed C–S bond electrosynthesis protocols, discussing and highlighting reaction features, substrate scope, as well as its application in pharmaceuticals, and the underlying reaction mechanisms. The study helps the development of electrochemical process-enabled C–S bond construction reactions in the future.
{"title":"Electrochemical Construction of C–S Bond: A Green Approach for Preparing Sulfur-Containing Scaffolds","authors":"Ruonan Zou, Jingbo Yu, P. Ying","doi":"10.1055/s-0044-1780505","DOIUrl":"https://doi.org/10.1055/s-0044-1780505","url":null,"abstract":"The organosulfur frameworks containing C–S bonds are important structural motifs in various biologically active molecules and functional materials. In this regard, transition-metal catalysis using chemical oxidants to prime reactions has emerged as the most common method, however, is prone to several side reactions such as dimerization and overoxidation. In recent years, organic electrosynthesis has become a hot topic due to its eco-friendly and mild process in which costly catalysts and toxic oxidants could be replaced by electrons. This perspective summarized the recently developed C–S bond electrosynthesis protocols, discussing and highlighting reaction features, substrate scope, as well as its application in pharmaceuticals, and the underlying reaction mechanisms. The study helps the development of electrochemical process-enabled C–S bond construction reactions in the future.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"8 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140272002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Granisetron hydrochloride can be used to prevent and treat nausea and vomiting induced by chemotherapy. Its prolonged half-life and reduced dose requirement improve patient acceptance. However, patients undergoing chemotherapy often suffer from dysphagia and drug spitting due to emesis. Hence, the development of a patient-centered formulation of granisetron hydrochloride with simple medication and high compliance is crucial. The current study employed a polymer combination of polyvinylpyrrolidone/polyvinyl alcohol (PVP/PVA) as film-forming materials and Lycoat® RS 780 as a disintegrant to formulate orodispersible films (ODFs) loaded with granisetron hydrochloride. Guided by the concept of quality by design, the quality target product profile and critical quality attributes (CQAs) for the ODF were defined. Through the quality risk assessment, essential factors that have a significant impact on CQAs were identified. The formulation was screened using the Box–Behnken statistical design with three factors and three levels. Our data suggested that all ODF formulations exhibited a disintegration time of less than 60 seconds and complete dissolution within 5 minutes. Furthermore, the formulation displayed appropriate mechanical properties, water residue, and pH values. Thus, the granisetron hydrochloride-loaded ODF is regarded as a patient-friendly formulation that enhances compliance and consequently aids in therapeutic effectiveness.
{"title":"Quality by Design Approach for Development and Characterization of Granisetron Hydrochloride-Loaded Orodispersible Films","authors":"Ming-Yan Li, Bing Wang, Jun-Qi Zhang, Liu-Liu Yang, Jun-Tao He, Fang Chen","doi":"10.1055/s-0043-1777043","DOIUrl":"https://doi.org/10.1055/s-0043-1777043","url":null,"abstract":"Granisetron hydrochloride can be used to prevent and treat nausea and vomiting induced by chemotherapy. Its prolonged half-life and reduced dose requirement improve patient acceptance. However, patients undergoing chemotherapy often suffer from dysphagia and drug spitting due to emesis. Hence, the development of a patient-centered formulation of granisetron hydrochloride with simple medication and high compliance is crucial. The current study employed a polymer combination of polyvinylpyrrolidone/polyvinyl alcohol (PVP/PVA) as film-forming materials and Lycoat® RS 780 as a disintegrant to formulate orodispersible films (ODFs) loaded with granisetron hydrochloride. Guided by the concept of quality by design, the quality target product profile and critical quality attributes (CQAs) for the ODF were defined. Through the quality risk assessment, essential factors that have a significant impact on CQAs were identified. The formulation was screened using the Box–Behnken statistical design with three factors and three levels. Our data suggested that all ODF formulations exhibited a disintegration time of less than 60 seconds and complete dissolution within 5 minutes. Furthermore, the formulation displayed appropriate mechanical properties, water residue, and pH values. Thus, the granisetron hydrochloride-loaded ODF is regarded as a patient-friendly formulation that enhances compliance and consequently aids in therapeutic effectiveness.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":" 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138617465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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