ChemMedChem最新文献_第7页

α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML. α- 三唑硼酸：针对急性髓细胞白血病 FLT3 的新型支架。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-09-27 DOI: 10.1002/cmdc.202400622

M L Introvigne, L Destro, L Mologni, V Crippa, P Zardi, F Fini, L F Prati, E Caselli, A Zambon

{"title":"α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML.","authors":"M L Introvigne, L Destro, L Mologni, V Crippa, P Zardi, F Fini, L F Prati, E Caselli, A Zambon","doi":"10.1002/cmdc.202400622","DOIUrl":"10.1002/cmdc.202400622","url":null,"abstract":"The treatment of acute myeloid leukemia (AML) presents a challenge to current therapies because of the development of drug resistance. Genetic mutation of FMS-like tyrosine kinase-3 (FLT3) is a target of interest for AML treatment, but the use of FLT3-targeting agents on AML patients has so far resulted in poor overall clinical outcomes.[1] The incorporation of the boronic group in a drug scaffold could enhance the bioavailability and pharmacokinetic profile of conventional anticancer chemotypes. Boronic acids represent an intriguing and unexplored class of compounds in the context of AML, and they are only scantly reported as inhibitors of protein kinases. We identified α-triazolylboronic acids as a novel chemotype for targeting FLT3 by screening a library of structurally heterogeneous in-house boronic acids. Selected compounds show low micromolar activities on enzymatic and cellular assays, selectivity against control cell lines and a recurring binding mode in in-silico studies. Furthermore, control analogues synthesized ad hoc and lacking the boronic acid are inactive, confirming that this group is essential for the activity of the series. All together, these results suggest α-triazolylboronic acids could be a promising novel chemotype for FLT3 inhibition, laying the ground for the design of further compounds.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400622"},"PeriodicalIF":3.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337828","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}

引用次数: 0

Lasamide Containing Sulfonylpiperazines as Effective Agents for the Management of Glaucoma Associated Symptoms 含磺酰基哌嗪的拉扎酰胺是治疗青光眼相关症状的有效药物

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-25 DOI: 10.1002/cmdc.202400601

fabrizio carta, Jaydeo T. Kilbile, Suryakant B. Sapkal, Gioele Renzi, Ilaria D’Agostino, Mohamed Boudjelal, Yasinalli Tamboli, Luigi Cutarella, Mattia Mori, Silvia Sgambellone, Serafina Villano, Silvia Marri, Laura Lucarini, Simone Carradori, Claudiu T. Supuran

引用次数: 0

The Role of Protein Disulfide Isomerase Inhibitors in Cancer Therapy 蛋白二硫异构酶抑制剂在癌症治疗中的作用

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-25 DOI: 10.1002/cmdc.202400590

Qiuying Nie, Junwei Yang, Xiedong Zhou, Na Li, Junmin Zhang

{"title":"The Role of Protein Disulfide Isomerase Inhibitors in Cancer Therapy","authors":"Qiuying Nie, Junwei Yang, Xiedong Zhou, Na Li, Junmin Zhang","doi":"10.1002/cmdc.202400590","DOIUrl":"https://doi.org/10.1002/cmdc.202400590","url":null,"abstract":"Protein disulfide isomerase (PDI) is a member of the mercaptan isomerase family, primarily located in the endoplasmic reticulum (ER). At least 21 PDI family members have been identified. PDI plays a key role in protein folding, correcting misfolded proteins, and catalyzing disulfide bond formation, rearrangement, and breaking. It also acts as a molecular chaperone. Dysregulation of PDI activity is thus linked to diseases such as cancer, infections, immune disorders, thrombosis, neurodegenerative diseases, and metabolic disorders. In particular, elevated intracellular PDI levels can enhance cancer cell proliferation, metastasis, and invasion, making it a potential cancer marker. Cancer cells require extensive protein synthesis, with disulfide bond formation by PDI being a critical producer. Thus, cancer cells have higher PDI levels than normal cells. Targeting PDI can induce ER stress and activate the Unfolded Protein Response (UPR) pathway, leading to cancer cell apoptosis. This review discusses the structure and function of PDI, PDI inhibitors in cancer therapy, and the limitations of current inhibitors, proposing especially future directions for developing new PDI inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"30 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317799","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}

引用次数: 0

Synthesis and Structure-Activity Relationship Analysis of 2-Substituted-1,2,4-Triazolo[1,5-a]Pyrimidin-7-Ones and their 6-Carboxylate Derivatives as Xanthine Oxidase Inhibitors. 作为黄嘌呤氧化酶抑制剂的 2-取代-1,2,4-三唑并[1,5-a]嘧啶-7-酮及其 6-羧酸衍生物的合成和结构-活性关系分析。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-09-24 DOI: 10.1002/cmdc.202400598

Giuseppe Luna, Anton V Dolzhenko, Ricardo L Mancera

{"title":"Synthesis and Structure-Activity Relationship Analysis of 2-Substituted-1,2,4-Triazolo[1,5-a]Pyrimidin-7-Ones and their 6-Carboxylate Derivatives as Xanthine Oxidase Inhibitors.","authors":"Giuseppe Luna, Anton V Dolzhenko, Ricardo L Mancera","doi":"10.1002/cmdc.202400598","DOIUrl":"10.1002/cmdc.202400598","url":null,"abstract":"Hyperuricemia is characterised by high blood levels of uric acid, and it can degenerate into gout when monosodium urate crystals precipitate in joints and other tissues. Uric acid is produced during the catabolism of xanthine by the enzyme xanthine oxidase (XO), which is the primary therapeutic target in gout treatment. Current XO inhibitors approved to treat gout, such as allopurinol and febuxostat, suffer from serious adverse effects, creating the need for new drug molecules. Three libraries comprising 75 purine analogues were designed using a 1,2,4-triazolo[1,5-a]pyrimidine scaffold, synthesised and tested in vitro as potential XO inhibitors. The screening identified that 23 compounds exhibited better inhibitory activity than allopurinol, with 2-(4-isopropoxyphenyl)-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid being 23 times more potent. Enzyme kinetics studies and molecular docking simulations were performed on the most active compounds to identify the mechanism of action and intermolecular interactions between the active site of XO and the inhibitors. The most potent compounds exhibited a mix-type inhibition mechanism and were predicted to interact with the same amino acid residues as allopurinol. These novel purine analogues are promising hits for further new lead development among purine-like drug XO inhibitors with therapeutic potential in the treatment of hyperuricemia and associated diseases.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400598"},"PeriodicalIF":3.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337827","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}

引用次数: 0

Synthesis and Biological Evaluation of N-(1H-Indol-6-ylmethyl)benzenesulfonamide Analogs as Metabolic Inhibitors of Mitochondrial ATP Production in Pancreatic Cancer Cells. 作为胰腺癌细胞线粒体 ATP 生成代谢抑制剂的 N-(1H-吲哚-6-基甲基)苯磺酰胺类似物的合成与生物学评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-09-24 DOI: 10.1002/cmdc.202400536

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

引用次数: 0

We are MedChem: The Frontiers in Medicinal Chemistry 2024. 我们是 MedChem：2024 年药物化学前沿。

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-09-23 DOI: 10.1002/cmdc.202400543

Matthias Schiedel, Philipp Barbie, Felix Pape, Marta Pinto, Andrea Unzue Lopez, María Méndez, Gerhard Hessler, Daniel Merk, Matthias Gehringer, Christina Lamers

引用次数: 0

Evaluation of a Radioiodinated G-quadruplex Binder in Cervical Cancer Models 在宫颈癌模型中评估放射性碘化 G-四联粘合剂

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-20 DOI: 10.1002/cmdc.202400438

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

{"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":"203 1","pages":""},"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}

引用次数: 0

Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling 利用分子建模探索分枝杆菌氧化磷酸化抑制剂的化学空间

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-20 DOI: 10.1002/cmdc.202400303

Islam K. Matar, Zhongmin Dong, Chérif F. Matta

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Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein 发现 KW0113 是首个有效的 DNMT1 蛋白 PROTAC 降解剂

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-20 DOI: 10.1002/cmdc.202400467

Huihui Wang, Zhaoliang Wang, Linghao Hu, Bingjie Yang, Liangyi Zong, Dounan Xu, Bo Yu, Xiangqian Kong, Mingliang Wang

引用次数: 0

Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat 已获批准的 HIF 脯氨酰羟化酶抑制剂 Desidustat 和 Enarodustat 的晶体学和选择性研究

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-18 DOI: 10.1002/cmdc.202400504

Thomas P. Corner, Eidarus Salah, Anthony Tumber, Samanpreet Kaur, Yu Nakashima, Mark D. Allen, Lara I. Schnaubelt, Giorgia Fiorini, Lennart Brewitz, Christopher Schofield

{"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":"8 1","pages":""},"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}

引用次数: 0