MedChemComm最新文献_第10页

Copper selective 8-aminoquinoline based tetradentate chelators as anticancer agents 作为抗癌剂的铜选择性 8-氨基喹啉基四价螯合剂

IF 3.597

MedChemComm Pub Date : 2024-06-04 DOI: 10.1039/D4MD00171K

Yingzhen Guan, Michel Nguyen, Anne Robert, Yan Liu and Bernard Meunier

{"title":"Copper selective 8-aminoquinoline based tetradentate chelators as anticancer agents","authors":"Yingzhen Guan, Michel Nguyen, Anne Robert, Yan Liu and Bernard Meunier","doi":"10.1039/D4MD00171K","DOIUrl":"10.1039/D4MD00171K","url":null,"abstract":"Cancer cell proliferation and metastasis are known to be dependent on angiogenesis which is regulated by several parameters including copper availability. Tetradentate monoquinoline (TDMQ) ligands constitute a series of chelators tailored to regulate copper homeostasis due to their specificity for copper(II) with respect to Cu(I) or other biometals like iron or zinc. One of these chelators, TDMQ20 efficiently inhibits both proliferation and migration of several human cancer cell lines, better than the reference drug 5-fluorouracil, and with higher selectivity indexes with respect to non-cancer human cells. The biological activity of TDMQ20 may be driven by the coordination chemistry of copper, and the ability of this chelator to restore copper homeostasis and its subsequent redox properties. The anticancer mechanism of action of TDMQ20 involves intracellular production of reactive oxygen species, drastic mitochondrial damages and induction of tumor cell apoptosis. These data support the selection of TDMQ20 as drug-candidate against several human cancers.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 3048-3056"},"PeriodicalIF":3.597,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00171k?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells† 磷酸抗原的膦酰二胺原药（ProPAgens）具有强效的 Vγ9/Vδ2 T 细胞活化和消灭癌细胞的作用

IF 3.597

MedChemComm Pub Date : 2024-06-03 DOI: 10.1039/D4MD00208C

Qin Xu, Maria Sharif, Edward James, Jack O. Dismorr, James H. R. Tucker, Benjamin E. Willcox and Youcef Mehellou

{"title":"Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells†","authors":"Qin Xu, Maria Sharif, Edward James, Jack O. Dismorr, James H. R. Tucker, Benjamin E. Willcox and Youcef Mehellou","doi":"10.1039/D4MD00208C","DOIUrl":"10.1039/D4MD00208C","url":null,"abstract":"The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2462-2473"},"PeriodicalIF":3.597,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00208c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141531763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Leveraging bounded datapoints to classify molecular potency improvements† 利用有界数据点对分子效力改进进行分类

IF 3.597

MedChemComm Pub Date : 2024-05-31 DOI: 10.1039/D4MD00325J

Zachary Fralish, Paul Skaluba and Daniel Reker

{"title":"Leveraging bounded datapoints to classify molecular potency improvements†","authors":"Zachary Fralish, Paul Skaluba and Daniel Reker","doi":"10.1039/D4MD00325J","DOIUrl":"10.1039/D4MD00325J","url":null,"abstract":"Molecular machine learning algorithms are becoming increasingly powerful at predicting the potency of potential drug candidates to guide molecular discovery, lead series prioritization, and structural optimization. However, a substantial amount of inhibition data is bounded and inaccessible to traditional regression algorithms. Here, we develop a novel molecular pairing approach to process this data. This creates a new classification task of predicting which one of two paired molecules is more potent. This novel classification task can be accurately solved by various, established molecular machine learning algorithms, including XGBoost and Chemprop. Across 230 ChEMBL IC50 datasets, both tree-based and neural network-based “DeltaClassifiers” show improvements over traditional regression approaches in correctly classifying molecular potency improvements. The Chemprop-based deep DeltaClassifier outperformed all here evaluated regression approaches for paired molecules with shared and with distinct scaffolds, highlighting the promise of this approach for molecular optimization and scaffold-hopping.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2474-2482"},"PeriodicalIF":3.597,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00325j?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141190404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of atropisomerism on a non-steroidal glucocorticoid receptor agonist† 阿托品异构对一种非甾体糖皮质激素受体激动剂的影响

IF 3.597

MedChemComm Pub Date : 2024-05-31 DOI: 10.1039/D4MD00245H

Zhou Xu, Zhongyuan Wang, Xiaona Shi, Rui Ding, Li Han, Xueping Yang, Hongmei Zhang and Adrian D. Hobson

引用次数: 0

Systematic computational strategies for identifying protein targets and lead discovery 识别蛋白质靶标和发现先导物的系统计算策略

IF 3.597

MedChemComm Pub Date : 2024-05-31 DOI: 10.1039/D4MD00223G

Arti Kataria, Ankit Srivastava, Desh Deepak Singh, Shafiul Haque, Ihn Han and Dharmendra Kumar Yadav

引用次数: 0

Novel flexible biphenyl PfDHFR inhibitors with improved antimalarial activity† 具有更好抗疟活性的新型柔性联苯 PfDHFR 抑制剂

IF 3.597

MedChemComm Pub Date : 2024-05-30 DOI: 10.1039/D4MD00197D

Sasithorn Decharuangsilp, Uthai Arwon, Nawarat Sooksai, Roonglawan Rattanajak, Thanaya Saeyang, Danoo Vitsupakorn, Jarunee Vanichtanankul, Yongyuth Yuthavong, Sumalee Kamchonwongpaisan and Marie Hoarau

引用次数: 0

Targeted suppression of oral squamous cell carcinoma by pyrimidine-tethered quinoxaline derivatives† 嘧啶系喹喔啉衍生物对口腔鳞状细胞癌的靶向抑制作用

IF 3.597

MedChemComm Pub Date : 2024-05-24 DOI: 10.1039/D4MD00042K

Asmita Choithramani, Rudradip Das, Gourav Bothra, Priyanka Patel Vatsa, Venkatesh Muthukumar, Bombothu Kavya Sai Bhuvana, Saumya Kapoor, Deepshika Moola, Moumita Ghosh Chowdhury, Amit Mandoli and Amit Shard

{"title":"Targeted suppression of oral squamous cell carcinoma by pyrimidine-tethered quinoxaline derivatives†","authors":"Asmita Choithramani, Rudradip Das, Gourav Bothra, Priyanka Patel Vatsa, Venkatesh Muthukumar, Bombothu Kavya Sai Bhuvana, Saumya Kapoor, Deepshika Moola, Moumita Ghosh Chowdhury, Amit Mandoli and Amit Shard","doi":"10.1039/D4MD00042K","DOIUrl":"10.1039/D4MD00042K","url":null,"abstract":"Oral cancer (OC) stands as a prominent cause of global mortality. Despite numerous efforts in recent decades, the efficacy of novel therapies to extend the lifespan of OC patients remains disappointingly low. Consequently, the demand for innovative therapeutic agents has become all the more pressing. In this context, we present our work on the design and synthesis of twenty-five novel quinoxaline-tethered imidazopyri(mi)dine derivatives. This was followed by comprehensive investigations into the impact of these molecules on the OC cell line. The in vitro cytotoxicity studies performed in CAL-27 and normal oral epithelial (NOE) cell lines revealed that some of the synthesized molecules like 12d have potent antiproliferative activity specifically towards OC cells with an IC50 of 0.79 μM and show negligible cytotoxicity over NOE cells. Further, 12d arrested cell growth in the S phase of the cell cycle and induced cell death by early apoptosis. The in silico studies validated that 12d binds to the activator binding site on pyruvate kinase M2 (PKM2) overexpressed in OC while the lactate dehydrogenase (LDH)-coupled enzyme assay established 12d as a potent PKM2 activator with an AC50 of 0.6 nM. Hence, this study provides fruitful evidence for the designed compounds as anticancer agents against OC.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 2729-2744"},"PeriodicalIF":3.597,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141568321","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}

引用次数: 0

Identification of lysosomotropism using explainable machine learning and morphological profiling cell painting data† 利用可解释的机器学习和形态剖析细胞绘画数据识别溶酶体运动

IF 3.597

MedChemComm Pub Date : 2024-05-24 DOI: 10.1039/D4MD00107A

Aishvarya Tandon, Anna Santura, Herbert Waldmann, Axel Pahl and Paul Czodrowski

引用次数: 0

Fragment-based drug discovery campaigns guided by native mass spectrometry 以原生质谱为指导的片段药物发现活动

IF 3.597

MedChemComm Pub Date : 2024-05-22 DOI: 10.1039/D4MD00273C

Louise M. Sternicki and Sally-Ann Poulsen

引用次数: 0

New melphalan derivatives for the treatment of retinoblastoma in combination with thermotherapy† 结合热疗治疗视网膜母细胞瘤的新型美法仑衍生物

IF 3.597

MedChemComm Pub Date : 2024-05-21 DOI: 10.1039/D4MD00211C

Soumaila Zebret, Mouna Hadiji, Jan Romano-deGea, Aurélien Bornet, Daniel Ortiz, Farzaneh Fadaei-Tirani, Christina Stathopoulos, Patrycja Nowak-Sliwinska, Francis L. Munier and Paul J. Dyson

引用次数: 0