Journal of Medicinal Chemistry最新文献_第2页

New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells. 新的线粒体靶向鱼藤素衍生物会影响药物诱导的衰老乳腺癌细胞的丝裂吞噬功能并限制其存活。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-25 DOI: 10.1021/acs.jmedchem.4c01664

Iwona Rzeszutek,Martyna Cybularczyk-Cecotka,Anna Deręgowska,Paulina Stec,Maciej Wnuk,Olga Kołodziej,Joanna Kałafut,Anna Wawruszak,Wojciech Witkowski,Grzegorz Litwinienko,Anna Lewińska

{"title":"New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells.","authors":"Iwona Rzeszutek,Martyna Cybularczyk-Cecotka,Anna Deręgowska,Paulina Stec,Maciej Wnuk,Olga Kołodziej,Joanna Kałafut,Anna Wawruszak,Wojciech Witkowski,Grzegorz Litwinienko,Anna Lewińska","doi":"10.1021/acs.jmedchem.4c01664","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01664","url":null,"abstract":"Mitochondria are considered as promising targets for cancer treatment. In the present study, triphenyl phosphonium cationic group-conjugated fisetin (mito-fisetin) was synthesized, and its anticancer activity was investigated in several cellular models of estrogen receptor (ER)-positive breast cancer in vitro and in vivo in proliferating and tamoxifen-promoted senescent states. Mito-fisetin, when used at low micromolar concentrations, stimulated the dissipation of mitochondrial membrane potential and oxidative stress, and affected mitochondrial function, resulting in apoptosis induction in senescent breast cancer cells. Mito-fisetin-mediated cytotoxicity was due to increased levels of phosphorylated AMPK, decreased levels of AKT and HSP90, and impaired mitophagic response, as judged by the analysis of the markers of mitophagosome formation. Senescent breast cancer cells were found to be more sensitive to mito-fisetin treatment than proliferating ones. We postulate that mitochondrial targeting in the case of fisetin may be considered as a promising anticancer and senotherapeutic strategy to eliminate drug-resistant senescent breast cancer cells.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Boosting Med Chem Education: Integrating Biology for Drug Discovery Talents. 促进医学化学教育：整合生物学，培养药物发现人才。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-24 DOI: 10.1021/acs.jmedchem.4c02208

Qiu Sun, Liang Ouyang

引用次数: 0

A Highly Atom-Efficient Prodrug Approach to Generate Synergy between H2S and Nonsteroidal Anti-inflammatory Drugs and Improve Safety 原子效率高的原药方法使 H2S 和非甾体抗炎药产生协同作用并提高安全性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-24 DOI: 10.1021/acs.jmedchem.4c01254

Wen Peng, Lixiao Qin, Tianci Wang, Yangqian Sun, Zhen Li, David J. Lefer, Cheng Luo, Fei Ye, Binghe Wang, Weiwei Guo, Yueqin Zheng

{"title":"A Highly Atom-Efficient Prodrug Approach to Generate Synergy between H2S and Nonsteroidal Anti-inflammatory Drugs and Improve Safety","authors":"Wen Peng, Lixiao Qin, Tianci Wang, Yangqian Sun, Zhen Li, David J. Lefer, Cheng Luo, Fei Ye, Binghe Wang, Weiwei Guo, Yueqin Zheng","doi":"10.1021/acs.jmedchem.4c01254","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01254","url":null,"abstract":"Efforts to synergize hydrogen sulfide (H2S) with NSAIDs have faced challenges due to complex structural entities and independent release kinetics. This study presents a highly atom-efficient approach of using a thiocarboxylic acid (thioacid) as a novel H2S releasing precursor and successfully employs it to modify NSAIDs, which offers several critical advantages. First, thioacid-modified NSAID is active in inhibiting cyclooxygenase, sometimes with improved potency. Second, this prodrug approach avoids introducing extra structural moieties, allowing for the release of only the intended active principals. Third, the release of H2S and NSAID is concomitant, thus optimally synchronizing the concentration profiles of the two active principals. The design is based on our discovery that esterases can directly and efficiently hydrolyze thiocarboxylic acids, enabling controlled release H2S. This study demonstrates the proof of principle through synthesizing analogs, assesses release kinetics, enzyme inhibition, and pharmacological efficacy, and evaluates toxicity and gut microbiota regulation in animal models.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Career Transitions That Require a Lot of Energy and Take You to Excited States Will Eventually Result in Brighter Professional Achievements. 职业转型需要大量精力，会让你进入兴奋状态，最终会取得更辉煌的职业成就。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-24 DOI: 10.1021/acs.jmedchem.4c02145

Cristiano R W Guimarães

引用次数: 0

New Applications of Sulfonyl Fluorides: A Microcosm of the Deep Integration of Chemistry and Biology in Drug Design. 磺酰氟的新应用：药物设计中化学与生物学深度融合的一个缩影。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-24 DOI: 10.1021/acs.jmedchem.4c02112

Shaoqing Du, Xueping Hu, Craig W Lindsley, Peng Zhan

引用次数: 0

Computationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia. 计算驱动发现对多药耐药慢性髓性白血病有疗效的 BCR-ABL1 激酶抑制剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-23 DOI: 10.1021/acs.jmedchem.4c01852

Jarvis Hill, R Houston Givhan, Bin Yi, Robert M Jones, Eugene F Douglass, Yaguang Xi, Henry F Schaefer, David Crich

{"title":"Computationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia.","authors":"Jarvis Hill, R Houston Givhan, Bin Yi, Robert M Jones, Eugene F Douglass, Yaguang Xi, Henry F Schaefer, David Crich","doi":"10.1021/acs.jmedchem.4c01852","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01852","url":null,"abstract":"The permeability glycoprotein, encoded by the ABCB1 gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate that the P-gp-mediated efflux ratio can be minimized by computationally driven optimization of the molecular dipole and/or cpKa without recourse to intramolecular hydrogen bonds.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease. 发现一种强效、口服活性和长效 P2X7 受体拮抗剂，作为延缓慢性肾病进展的临床前候选药物。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-23 DOI: 10.1021/acs.jmedchem.4c01395

Ruijia Zhang, Kaiyue Su, Letian Yang, Huaichuan Duan, Lei Tang, Minghai Tang, Min Zhao, Neng Ye, Xiaoying Cai, Xueqin Jiang, Na Li, Jing Peng, Xinlu Zhang, Lingkai Tang, Qiang Qiu, Lijuan Chen, Wenshuang Wu, Jianping Hu, Liang Ma, Haoyu Ye

{"title":"Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease.","authors":"Ruijia Zhang, Kaiyue Su, Letian Yang, Huaichuan Duan, Lei Tang, Minghai Tang, Min Zhao, Neng Ye, Xiaoying Cai, Xueqin Jiang, Na Li, Jing Peng, Xinlu Zhang, Lingkai Tang, Qiang Qiu, Lijuan Chen, Wenshuang Wu, Jianping Hu, Liang Ma, Haoyu Ye","doi":"10.1021/acs.jmedchem.4c01395","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01395","url":null,"abstract":"Chronic kidney disease (CKD) is a condition characterized by functional deterioration with sustained inflammation and progressive fibrosis of the kidneys affecting over 800 million people worldwide. The P2X7 receptor (P2X7R) plays a key role in CKD progression. Our previous P2X7R antagonists demonstrated good efficacy for treating kidney injury but were limited by low oral exposure and short half-life, restricting their application. This study reports the optimization of P2X7R antagonists for better oral pharmacokinetics. The candidate compound 13a with the respective IC50 of 34.86 and 25.28 nM against human and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits a remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55 μg·h/L. Oral administration of 13a (0.3 or 1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis in unilateral ureteral obstruction and adenine diet-induced mice models, highlighting its potential for delaying the progression of CKD.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Use of the Novel Site-Directed Enzyme Enhancement Therapy (SEE-Tx) Drug Discovery Platform to Identify Pharmacological Chaperones for Glutaric Acidemia Type 1 利用新颖的定点酶强化疗法（SEE-Tx）药物发现平台确定治疗 1 型戊二酸血症的药理合剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-23 DOI: 10.1021/acs.jmedchem.4c00292

Madalena Barroso, Alexandra Puchwein-Schwepcke, Lars Buettner, Ingrid Goebel, Katrin Küchler, Ania C. Muntau, Aida Delgado, Ana M. Garcia-Collazo, Marc Martinell, Xavier Barril, Elena Cubero, Søren W. Gersting

{"title":"Use of the Novel Site-Directed Enzyme Enhancement Therapy (SEE-Tx) Drug Discovery Platform to Identify Pharmacological Chaperones for Glutaric Acidemia Type 1","authors":"Madalena Barroso, Alexandra Puchwein-Schwepcke, Lars Buettner, Ingrid Goebel, Katrin Küchler, Ania C. Muntau, Aida Delgado, Ana M. Garcia-Collazo, Marc Martinell, Xavier Barril, Elena Cubero, Søren W. Gersting","doi":"10.1021/acs.jmedchem.4c00292","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00292","url":null,"abstract":"Allosteric regulators acting as pharmacological chaperones hold promise for innovative therapeutics since they target noncatalytic sites and stabilize the folded protein without competing with the natural substrate, resulting in a net gain of function. Exogenous allosteric regulators are typically more selective than active site inhibitors and can be more potent than competitive inhibitors when the natural substrate levels are high. To identify novel structure-targeted allosteric regulators (STARs) that bind to and stabilize the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed enzyme enhancement therapy (SEE-Tx) technology was applied. SEE-Tx is an innovative drug discovery platform with the potential to identify drugs for treating protein misfolding disorders, such as glutaric acidemia type 1 (GA1) disease. Putative allosteric regulators were discovered using structure- and ligand-based virtual screening methods and validated using orthogonal biophysical and biochemical assays. The computational approach presented here could be used to discover allosteric regulators of other protein misfolding disorders.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Ruthenium(ii)–Arene Complex Triggers Immunogenic Ferroptosis for Reversing Drug Resistance 钌(ii)-芘复合物触发免疫性铁跃迁以逆转耐药性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-23 DOI: 10.1021/acs.jmedchem.4c01467

Mengdi Lv, Yue Zheng, Xiangyu Dai, Jingyue Zhao, Guojing Hu, Meng Ren, Zhengqi Shen, Zhi Su, Chao Wu, Hong-Ke Liu, Xuling Xue, Zong-Wan Mao

{"title":"Ruthenium(ii)–Arene Complex Triggers Immunogenic Ferroptosis for Reversing Drug Resistance","authors":"Mengdi Lv, Yue Zheng, Xiangyu Dai, Jingyue Zhao, Guojing Hu, Meng Ren, Zhengqi Shen, Zhi Su, Chao Wu, Hong-Ke Liu, Xuling Xue, Zong-Wan Mao","doi":"10.1021/acs.jmedchem.4c01467","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01467","url":null,"abstract":"Chemoresistance remains an arduous challenge in oncology, but ferroptosis shows potential for overcoming it by stimulating the immune system. Herein, a novel high-performance ruthenium(II)-based arene complex [Ru(η6-p-cym)(BTBpy)Cl] (RuBTB) is developed for ferroptosis-enhanced antitumor immunity and drug resistance reversal via glutathione (GSH) metabolism imbalance. RuBTB shows significantly enhanced antiproliferation activity against cisplatin (CDDP)-resistant lung cancer cells (A549R), with 26.35-fold better anticancer effects than CDDP. Immunogenic ferroptosis is induced by GSH depletion/glutathione peroxidase 4 (GPX4) inactivation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in RuBTB-treated cells. Mechanism studies indicate that RuBTB regulates ferroptosis and immune-related pathways, coordinating with GSH metabolism-mediated glutathione S-transferase (GST) inhibition to reverse drug resistance in platinum-combined therapy. Tumor vaccination experiments demonstrate the intensified antitumor effects endowed by highly immunogenic ferroptosis in vivo. This study provides the first example of a metal–arene complex for achieving satisfactory ferroptosis therapeutic effects with efficient immunogenicity to overcome drug resistance in metal-based immunochemotherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Novel 18F-Labeled Benzimidazolone-Based Radioligands as Highly Selective Sigma-2 Receptor Probes for Tumor Imaging 新型 18F 标记苯并咪唑酮类放射配体作为肿瘤成像的高选择性 Sigma-2 受体探针

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-23 DOI: 10.1021/acs.jmedchem.4c01315

Jingqi Wang, Tao Wang, Tiantian Mou, Tao Yang, Xu Gao, Xiaodan An, Biao Hu, Jinming Zhang, Xiaoli Zhang, Winnie Deuther-Conrad, Yiyun Huang, Hongmei Jia

{"title":"Novel 18F-Labeled Benzimidazolone-Based Radioligands as Highly Selective Sigma-2 Receptor Probes for Tumor Imaging","authors":"Jingqi Wang, Tao Wang, Tiantian Mou, Tao Yang, Xu Gao, Xiaodan An, Biao Hu, Jinming Zhang, Xiaoli Zhang, Winnie Deuther-Conrad, Yiyun Huang, Hongmei Jia","doi":"10.1021/acs.jmedchem.4c01315","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01315","url":null,"abstract":"Novel sigma-2 (σ2) receptor ligands with benzimidazolone and 5,6-dimethoxyisoindoline as pharmacophores were designed and synthesized. Compound 4 exhibited low nanomolar affinity for the σ2 receptors (Ki(σ2) = 2.30 nM) and high subtype selectivity (Ki(σ1)/Ki(σ2) > 1500). Radioligand [18F]4 was prepared in radiochemical yields of 18 ± 7%, with >99% radiochemical purity and molar activity of 244 ± 136 GBq/μmol. Biodistribution and blocking studies in mice and small animal PET/CT imaging in rats indicated highly specific binding of [18F]4 in organs known to express the σ2 receptors. Small animal PET/CT imaging with [18F]4 showed clear visualization of the tumors in subcutaneous A549 lung cancer and U87MG glioma xenografts, and intracranial orthotopic U87MG glioma models. Co-administration of CM398 with [18F]4 significantly reduced activity uptake in the tumors, indicating that [18F]4 specifically binds to the σ2 receptors expressed in A549 and U87MG xenografts.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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