Zachary C Brandeburg, Sakariyau A Waheed, Carina A Derewonko, Caroline E Dunn, Ethan C Pfeiffer, Ann Marie E Flusche, Robert J Sheaff, Angus A Lamar
A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-hour compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-hour compound exposure) assay developed within our laboratories. The IC50 values of the active compounds were determined using the rapid assay and six compounds displayed an IC50 value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display significant activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC50 value <5 μM against one or more pancreatic cancer cell lines.
{"title":"Synthesis and Biological Evaluation of N-(1H-Indol-6-ylmethyl)benzenesulfonamide Analogs as Metabolic Inhibitors of Mitochondrial ATP Production in Pancreatic Cancer Cells.","authors":"Zachary C Brandeburg, Sakariyau A Waheed, Carina A Derewonko, Caroline E Dunn, Ethan C Pfeiffer, Ann Marie E Flusche, Robert J Sheaff, Angus A Lamar","doi":"10.1002/cmdc.202400536","DOIUrl":"https://doi.org/10.1002/cmdc.202400536","url":null,"abstract":"<p><p>A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-hour compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-hour compound exposure) assay developed within our laboratories. The IC50 values of the active compounds were determined using the rapid assay and six compounds displayed an IC50 value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display significant activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC50 value <5 μM against one or more pancreatic cancer cell lines.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337826","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}
Matthias Schiedel, Philipp Barbie, Felix Pape, Marta Pinto, Andrea Unzue Lopez, María Méndez, Gerhard Hessler, Daniel Merk, Matthias Gehringer, Christina Lamers
The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17th to 20th 2024 in Munich. Co-organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs-Maximilians-University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four-day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 100 posters were presented in two highly interactive poster sessions.
{"title":"We are MedChem: The Frontiers in Medicinal Chemistry 2024.","authors":"Matthias Schiedel, Philipp Barbie, Felix Pape, Marta Pinto, Andrea Unzue Lopez, María Méndez, Gerhard Hessler, Daniel Merk, Matthias Gehringer, Christina Lamers","doi":"10.1002/cmdc.202400543","DOIUrl":"https://doi.org/10.1002/cmdc.202400543","url":null,"abstract":"<p><p>The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17<sup>th</sup> to 20<sup>th</sup> 2024 in Munich. Co-organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs-Maximilians-University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four-day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 100 posters were presented in two highly interactive poster sessions.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277555","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}
António Paulo, Maria Cristina Oliveira, Maria Paula Cabral Campello, Lurdes Gano, Paula Raposinho, Ana Belchior, Edgar Mendes, Catarina D. Silva, Jéssica Lopes-Nunes, Carla Cruz
We herein describe the radiosynthesis of a 125I-labeled acridine orange derivative ([125I]-C8), acting as a G-quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE-RPT) of cancer. [125I]-C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo-destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]-C8 strongly compromised the viability of HeLa cells in a dose-dependent manner, inducing non-repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA. Biodistribution studies in a murine HeLa xenograft model showed that [125I]-C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]-C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]-C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.
我们在本文中描述了一种 125I 标记的吖啶橙衍生物（[125I]-C8）的放射合成及其在宫颈癌模型中的生物学评估，旨在揭示其作为奥杰电子放射药物治疗（AE-RPT）癌症的放射性配体的潜力。[125I]-C8是通过[125I]碘-脱烷反应合成的，放射化学收率中等（约60%）。在宫颈癌 HeLa 细胞中对其进行的评估表明，这种放射性化合物具有明显的细胞内化作用，并在细胞核中蓄积。与这些结果一致，[125I]-C8 会以剂量依赖的方式严重损害 HeLa 细胞的活力，诱发不可修复的 DNA 损伤，这很可能是由于 125I 在 DNA 附近释放的 AE 所致。在小鼠 HeLa 异种移植模型中进行的生物分布研究表明，全身给药后，[125I]-C8 的血液清除速度快，体内稳定性高，但肿瘤摄取率低。在同一动物肿瘤模型中，[125I]-C8与AS1411适配体的超分子共轭物（[125I]-C8/AS1411）的血液清除率较慢，但肿瘤摄取率没有改善。要利用[125I]-C8的放射毒性来对付宫颈癌细胞，还需要研究其他策略，即基于替代纳米给药载体和/或瘤内注射方法的策略。
{"title":"Evaluation of a Radioiodinated G-quadruplex Binder in Cervical Cancer Models","authors":"António Paulo, Maria Cristina Oliveira, Maria Paula Cabral Campello, Lurdes Gano, Paula Raposinho, Ana Belchior, Edgar Mendes, Catarina D. Silva, Jéssica Lopes-Nunes, Carla Cruz","doi":"10.1002/cmdc.202400438","DOIUrl":"https://doi.org/10.1002/cmdc.202400438","url":null,"abstract":"We herein describe the radiosynthesis of a 125I-labeled acridine orange derivative ([125I]-C8), acting as a G-quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE-RPT) of cancer. [125I]-C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo-destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]-C8 strongly compromised the viability of HeLa cells in a dose-dependent manner, inducing non-repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA. Biodistribution studies in a murine HeLa xenograft model showed that [125I]-C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]-C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]-C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256292","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}
Intracellular pathogens are exceedingly clinically challenging, including pathogenic mycobacteria. Many global efforts are currently in action to battle these notorious disease agents. This review provides an overview of mycobacteria, along with their associated diseases, pathogenesis, and exploitable respiratory vulnerabilities to supplement contemporary antimycobacterial discovery.
{"title":"Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling","authors":"Islam K. Matar, Zhongmin Dong, Chérif F. Matta","doi":"10.1002/cmdc.202400303","DOIUrl":"https://doi.org/10.1002/cmdc.202400303","url":null,"abstract":"Intracellular pathogens are exceedingly clinically challenging, including pathogenic mycobacteria. Many global efforts are currently in action to battle these notorious disease agents. This review provides an overview of mycobacteria, along with their associated diseases, pathogenesis, and exploitable respiratory vulnerabilities to supplement contemporary antimycobacterial discovery.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268921","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}
Huihui Wang, Zhaoliang Wang, Linghao Hu, Bingjie Yang, Liangyi Zong, Dounan Xu, Bo Yu, Xiangqian Kong, Mingliang Wang
DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50 = 643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies.
{"title":"Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein","authors":"Huihui Wang, Zhaoliang Wang, Linghao Hu, Bingjie Yang, Liangyi Zong, Dounan Xu, Bo Yu, Xiangqian Kong, Mingliang Wang","doi":"10.1002/cmdc.202400467","DOIUrl":"https://doi.org/10.1002/cmdc.202400467","url":null,"abstract":"DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50 = 643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256293","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}
Thomas P. Corner, Eidarus Salah, Anthony Tumber, Samanpreet Kaur, Yu Nakashima, Mark D. Allen, Lara I. Schnaubelt, Giorgia Fiorini, Lennart Brewitz, Christopher Schofield
Prolyl hydroxylase domain‐containing proteins 1‐3 (PHD1‐3) are 2‐oxoglutarate (2OG)‐dependent oxygenases catalysing C‐4 hydroxylation of prolyl residues in α‐subunits of the heterodimeric transcription factor hypoxia‐inducible factor (HIF), modifications that promote HIF‐α degradation via the ubiquitin‐proteasome pathway. Pharmacological inhibition of the PHDs induces HIF‐α stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia‐inducible factor‐α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1‐3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA‐damage repair, and agrochemical resistance.
{"title":"Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat","authors":"Thomas P. Corner, Eidarus Salah, Anthony Tumber, Samanpreet Kaur, Yu Nakashima, Mark D. Allen, Lara I. Schnaubelt, Giorgia Fiorini, Lennart Brewitz, Christopher Schofield","doi":"10.1002/cmdc.202400504","DOIUrl":"https://doi.org/10.1002/cmdc.202400504","url":null,"abstract":"Prolyl hydroxylase domain‐containing proteins 1‐3 (PHD1‐3) are 2‐oxoglutarate (2OG)‐dependent oxygenases catalysing C‐4 hydroxylation of prolyl residues in α‐subunits of the heterodimeric transcription factor hypoxia‐inducible factor (HIF), modifications that promote HIF‐α degradation via the ubiquitin‐proteasome pathway. Pharmacological inhibition of the PHDs induces HIF‐α stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia‐inducible factor‐α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1‐3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA‐damage repair, and agrochemical resistance.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256294","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 bacterial cell membrane primarily houses lipids, carbohydrates, and proteins forming a barrier and interface that maintains cellular integrity, supports homeostasis, and senses environmental changes. Compared to lipid components and excreted secondary metabolites, compounds embedded in the producer cell membrane are often overlooked due to their low abundance and niche‐specific functions. The accumulation of findings has led to an increased appreciation of their crucial roles in bacterial cell biochemistry, physiology, and ecology, as well as their impact on mutualistic and pathogenic bacteria‐eukaryote interactions. This review highlights the structures, biosynthesis, regulation, and ecological functions of membrane‐embedded secondary metabolites. It also discusses antibiotics that target their biosynthetic pathways, aiming to inspire the development of antibiotics specific to pathogenic bacteria without harming human cells.
{"title":"Bacterial Secondary Metabolites Embedded in Producer Cell Membranes and Antibiotics Targeting Their Biosynthesis","authors":"Zhao Xia, Hao Xiang, Yi-Ming Shi","doi":"10.1002/cmdc.202400469","DOIUrl":"https://doi.org/10.1002/cmdc.202400469","url":null,"abstract":"The bacterial cell membrane primarily houses lipids, carbohydrates, and proteins forming a barrier and interface that maintains cellular integrity, supports homeostasis, and senses environmental changes. Compared to lipid components and excreted secondary metabolites, compounds embedded in the producer cell membrane are often overlooked due to their low abundance and niche‐specific functions. The accumulation of findings has led to an increased appreciation of their crucial roles in bacterial cell biochemistry, physiology, and ecology, as well as their impact on mutualistic and pathogenic bacteria‐eukaryote interactions. This review highlights the structures, biosynthesis, regulation, and ecological functions of membrane‐embedded secondary metabolites. It also discusses antibiotics that target their biosynthetic pathways, aiming to inspire the development of antibiotics specific to pathogenic bacteria without harming human cells.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256296","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}
Anca-Elena Dascălu, Christophe Furman, Steve Lancel, Emmanuelle Lipka, Maxime Liberelle, Eric Boulanger, Alina Ghinet
In the context of age-related disorders, the receptor of advanced glycation end products (RAGE), plays a pivotal role in the pathogenesis of these conditions by triggering downstream signaling pathways associated with chronic inflammation and oxidative stress. Targeting this inflammaging phenomenon with RAGE antagonists holds promise for interventions with broad implications in healthy aging and the management of age-related conditions. This study explores the structure-activity relationship (SAR) of pyrazoline-based RAGE antagonists synthesized using an ultrasound-assisted green one-pot two-steps methodology. Our investigation identifies phenylurenyl-pyrazoline 2g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC50 = 13 µM). Compound 2g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC50 = 22 µM) and favorable affinity in Microscale Thermophoresis (MST) assays (Kd = 17.1 µM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders.
{"title":"Ultrasound-Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE-Mediated Pathologies: Insights from SAR Studies and Biological Evaluations","authors":"Anca-Elena Dascălu, Christophe Furman, Steve Lancel, Emmanuelle Lipka, Maxime Liberelle, Eric Boulanger, Alina Ghinet","doi":"10.1002/cmdc.202400527","DOIUrl":"https://doi.org/10.1002/cmdc.202400527","url":null,"abstract":"In the context of age-related disorders, the receptor of advanced glycation end products (RAGE), plays a pivotal role in the pathogenesis of these conditions by triggering downstream signaling pathways associated with chronic inflammation and oxidative stress. Targeting this inflammaging phenomenon with RAGE antagonists holds promise for interventions with broad implications in healthy aging and the management of age-related conditions. This study explores the structure-activity relationship (SAR) of pyrazoline-based RAGE antagonists synthesized using an ultrasound-assisted green one-pot two-steps methodology. Our investigation identifies phenylurenyl-pyrazoline 2g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC50 = 13 µM). Compound 2g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC50 = 22 µM) and favorable affinity in Microscale Thermophoresis (MST) assays (Kd = 17.1 µM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268920","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}
Although Bosnia and Herzegovina has had a rich history in medicines and traditional medicines, it historically had poor activity regarding the field of medicinal chemistry in the country. However, this has changed recently as Bosnia and Herzegovina has shown immense potential in this field. A significant milestone occurred in 2019, with the establishment of the Organization Pharmaceutical Research Institute. This non‐governmental organization aims to improve medicinal chemistry in Bosnia and Herzegovina. Through research, partnerships, and educational initiatives, the organization has made substantial strides in promoting pharmaceutical research, education, and innovation. Moreover, the country‘s membership in the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) has further facilitated collaboration with European experts, access to cutting‐edge knowledge and technologies, and harmonization with European standards. Looking to the future, this organization endeavors to improve healthcare, encourage innovation in medicinal chemistry, and promote the development of new therapies. With the efforts to establish an Association of Chemists in Bosnia and Herzegovina, the nation‘s scientific community is poised to flourish, contributing to the advancement of medicinal chemistry and healthcare in the region.
{"title":"Medicinal Chemistry in Bosnia and Herzegovina ‐ Past, Present and Perspectives**","authors":"Martin Kondža","doi":"10.1002/cmdc.202400669","DOIUrl":"https://doi.org/10.1002/cmdc.202400669","url":null,"abstract":"Although Bosnia and Herzegovina has had a rich history in medicines and traditional medicines, it historically had poor activity regarding the field of medicinal chemistry in the country. However, this has changed recently as Bosnia and Herzegovina has shown immense potential in this field. A significant milestone occurred in 2019, with the establishment of the Organization Pharmaceutical Research Institute. This non‐governmental organization aims to improve medicinal chemistry in Bosnia and Herzegovina. Through research, partnerships, and educational initiatives, the organization has made substantial strides in promoting pharmaceutical research, education, and innovation. Moreover, the country‘s membership in the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) has further facilitated collaboration with European experts, access to cutting‐edge knowledge and technologies, and harmonization with European standards. Looking to the future, this organization endeavors to improve healthcare, encourage innovation in medicinal chemistry, and promote the development of new therapies. With the efforts to establish an Association of Chemists in Bosnia and Herzegovina, the nation‘s scientific community is poised to flourish, contributing to the advancement of medicinal chemistry and healthcare in the region.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256295","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}
Lukas Gardner, John Rossi, Brock Armstrong, Mia Muse, Alex LaVeck, Melanie A. Blevins, Lingdi Zhang, Dr. Heide L. Ford, Dr. Rui Zhao, Dr. Xiang Wang
Protein-ligand docking simulation showing hydrogen bonding in green and Pi-Pi stacking in cyan between EYA2 and a novel inhibitor. Several new interactions are found in this study leading to >30-fold increase of potency relative to the previous lead analog. Many analogs in the series expanded our knowledge on beneficial interactions between the protein and potential inhibitors. This new series of inhibitors provides further insight into treatment of many cancer lines including Glioblastoma and Medulloblastoma. More details can be found in article 10.1002/cmdc.202400179 by Heide L. Ford, Rui Zhao, Xiang Wang, and co-workers.
蛋白质-配体对接模拟显示 EYA2 与新型抑制剂之间的氢键（绿色）和 Pi-Pi 堆叠（青色）。这项研究发现了几种新的相互作用，与之前的先导类似物相比，其效力提高了 30 倍。该系列中的许多类似物扩展了我们对蛋白质与潜在抑制剂之间有益相互作用的了解。这一系列新的抑制剂为治疗包括胶质母细胞瘤和髓母细胞瘤在内的多种癌症提供了进一步的见解。更多详情请见 Heide L. Ford、Rui Zhao、Xiang Wang 及合作者撰写的文章 10.1002/cmdc.202400179。
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