Journal of Medicinal Chemistry最新文献

Cathepsin B-Activated Prodrug for Precision Tumor Theranostics. 组织蛋白酶b激活前药用于肿瘤精准治疗。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-03 DOI: 10.1021/acs.jmedchem.5c02241

Wenhao Zhai,Jiajun Li,Di Zhao,Ke Xu,Yuntai Liu,Debin Zheng,Zhizhong Wang

{"title":"Cathepsin B-Activated Prodrug for Precision Tumor Theranostics.","authors":"Wenhao Zhai,Jiajun Li,Di Zhao,Ke Xu,Yuntai Liu,Debin Zheng,Zhizhong Wang","doi":"10.1021/acs.jmedchem.5c02241","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02241","url":null,"abstract":"In response to the systemic toxicity associated with chemotherapeutic agents and the diverse characteristics of the tumor microenvironment, we present an innovative theranostic prodrug system, designated NM-001. NM-001 specifically targets the overexpressed integrin ανβ3 on tumor cells via the cRGD peptide, facilitating internalization into lysosomes. Subsequently, cathepsin B selectively cleaves the GFLG peptide, triggering an intramolecular self-elimination reaction that generates NM-002 with near-infrared (NIR) emission and releases chlorambucil (CLB). Concurrently, the fluorescence property undergoes a transition from green to NIR emission, enabling precise monitoring of the drug delivery and release process, thereby establishing a dual-channel optical feedback mechanism. This mechanism allows for real-time, in situ differentiation of drug delivery and release dynamics at the cellular level. Both in vitro and in vivo studies have demonstrated that NM-001 exhibits high selectivity and substantial antitumor efficacy against tumor cells, presenting a promising novel approach for personalized diagnosis and therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209273","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

Single-Dose Oral Influenza Antiviral Prodrug Enabled by Cholesterol Conjugation. 单剂量口服流感抗病毒前药由胆固醇偶联激活。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-03 DOI: 10.1021/acs.jmedchem.5c01808

Chenning Li,Xun Lv,Chenxi Cheng,Shuihong Cheng,Yiran Li,Yuhai Bi,Lifeng Fu,George Fu Gao,Xuebing Li

引用次数: 0

Optical Control of Leukotriene A4 Hydrolase Using Photoswitchable Inhibitors. 光开关抑制剂对白三烯A4水解酶的光学控制。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-03 DOI: 10.1021/acs.jmedchem.5c01654

Xin Zhou,Shumei Wang,Xingye Yang,Xin Zhang,Zhao Ma,Lupei Du,Minyong Li

引用次数: 0

Membrane Perturbations and Assay Interferences by Ivermectin Explain Its In Vitro SARS-CoV-2 Antiviral Activities and Lack of Translatability. 伊维菌素的膜扰动和检测干扰解释了其体外抗病毒活性和缺乏可翻译性。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-02 DOI: 10.1021/acs.jmedchem.5c01610

Richard T Eastman,Radda Rusinova,Karl F Herold,Xi-Ping Huang,Ty Voss,Alex D White,Hugh C Hemmings,Olaf S Andersen,Jayme L Dahlin

{"title":"Membrane Perturbations and Assay Interferences by Ivermectin Explain Its In Vitro SARS-CoV-2 Antiviral Activities and Lack of Translatability.","authors":"Richard T Eastman,Radda Rusinova,Karl F Herold,Xi-Ping Huang,Ty Voss,Alex D White,Hugh C Hemmings,Olaf S Andersen,Jayme L Dahlin","doi":"10.1021/acs.jmedchem.5c01610","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01610","url":null,"abstract":"The antiparasitic drug ivermectin was proposed as a repurposed drug for the treatment of SARS-CoV-2 infection based on in vitro studies, but proved ineffective in high-quality clinical trials. When exploring possible reasons for this disconnect, we found that ivermectin interferes with AlphaScreen assays by quenching singlet oxygen transmission, calling into question the original justifications for pursuing ivermectin as an antiviral agent. Furthermore, at the low micromolar concentrations where ivermectin reduced SARS-CoV-2 viral burden in vitro, ivermectin decreased cell viability, modified membrane bilayer properties, and nonspecifically dysregulated membrane protein functions. In this Perspective, we provide molecular-level rationale for why ivermectin, an effective and safe antiparasitic drug at low nanomolar concentrations, becomes cytotoxic at low micromolar concentrations and, in turn, why ivermectin has not translated into an effective antiviral agent. We highlight lessons learned from the failed ivermectin repurposing effort and provide a workflow for identifying membrane-perturbing bioactivity early in drug development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"157 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209275","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

Plasma Kallikrein Inhibitors for Multiple Disorders: Current Advances and Perspectives. 血浆钾likrein抑制剂治疗多种疾病：目前的进展和前景。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-02 DOI: 10.1021/acs.jmedchem.5c02234

Haonan Liu,Yujun Deng,Jiali Liu,Zhiwei Wang,Xue-Qin Hu,Yajun Duan,Yuanli Chen,Zhouling Xie

引用次数: 0

A Radiofluorinated Nanobody PET Tracer to Dynamically Visualize Differential Nectin4 Expression In Vivo. 放射性氟化纳米体PET示踪剂动态可视化体内差异Nectin4表达。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-02 DOI: 10.1021/acs.jmedchem.5c01260

Dongye Zheng,Yong Huang,Chengze Li,Yanye Lu,Zhaoheng Xie,Qiushi Ren,Ying Liang,Xiangxi Meng

引用次数: 0

Design and Synthesis of Senescence-Targeted Prodrugs with Senomorphic and Senolytic Properties To Mitigate Chemotherapy-Induced Kidney Injury. 抗衰老前药的设计与合成及其抗衰老特性减轻化疗引起的肾损伤。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-02 DOI: 10.1021/acs.jmedchem.5c01442

Lele Ding,Xi Wang,Qian Liu,Yuxuan Zhang,Xinyu Wu,Biying Xiao,Dan Liu,Lu Chen,Hairong Zeng,Bei Zhao,Changsheng Dong,Lihui Li,Guangbo Ge,Lijun Jia,Shuaishuai Ni

{"title":"Design and Synthesis of Senescence-Targeted Prodrugs with Senomorphic and Senolytic Properties To Mitigate Chemotherapy-Induced Kidney Injury.","authors":"Lele Ding,Xi Wang,Qian Liu,Yuxuan Zhang,Xinyu Wu,Biying Xiao,Dan Liu,Lu Chen,Hairong Zeng,Bei Zhao,Changsheng Dong,Lihui Li,Guangbo Ge,Lijun Jia,Shuaishuai Ni","doi":"10.1021/acs.jmedchem.5c01442","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01442","url":null,"abstract":"Senotherapeutic agents hold great potential for mitigating chemotherapy-induced kidney injury. However, the heterogeneity of cellular senescence complicates their application, as early stage senescent cells (SnCs) play beneficial roles in kidney damage repair. Senotherapeutics are broadly categorized into two classes: senolytics, which selectively eliminate SnCs, and senomorphics, which suppress the senescence-associated secretory phenotype (SASP) without killing them. Herein, we repurposed an antioxidant agent, bardoxolone methyl (CDDOMe), as a novel senomorphic agent to mitigate the chemotherapy-induced kidney injury and subsequently modified it into a series of senescence-associated β-galactosidase (SA-β-gal) activated prodrugs. The optimal prodrug, Gal-CDD-01, selectively induced apoptosis of the late-staged SnCs, while suppressing the senescence progression of early staged SnCs. Notably, Gal-CDD-01 possesses favorable efficacy and distribution selectivity in vivo, resulting in amelioration of motor functions in mice with kidney injury. Overall, this study presents a rational design for a dual-functional senescence-targeted prodrug and also explores its potential application in treating the chemotherapy-induced kidney injury.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"114 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209045","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

Thiazole-Based Tumor Pyruvate Kinase M2 Inhibitors: A Paradigm-Shifting Therapeutic Strategy Targeting Metabolic and Microbial Synergy in Colorectal Cancer. 以噻唑为基础的肿瘤丙酮酸激酶M2抑制剂：一种针对结直肠癌代谢和微生物协同作用的范式转移治疗策略。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1021/acs.jmedchem.5c02169

Moumita Ghosh Chowdhury,Aditya A Singh,Medha Bhattacharyya,Venkatesh Muthukumar,Saumya Kapoor,Akshay Srivastava,Hemant Kumar,Amit Shard

{"title":"Thiazole-Based Tumor Pyruvate Kinase M2 Inhibitors: A Paradigm-Shifting Therapeutic Strategy Targeting Metabolic and Microbial Synergy in Colorectal Cancer.","authors":"Moumita Ghosh Chowdhury,Aditya A Singh,Medha Bhattacharyya,Venkatesh Muthukumar,Saumya Kapoor,Akshay Srivastava,Hemant Kumar,Amit Shard","doi":"10.1021/acs.jmedchem.5c02169","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02169","url":null,"abstract":"Colorectal cancer (CRC) remains a major global health burden, with current treatments primarily focused on eradicating cancer cells. However, chemotherapy-induced gut dysbiosis exacerbates inflammation and disease progression, necessitating innovative therapeutic strategies. While various metabolic inhibitors and microbiome-modulating approaches have been explored separately, no reported agent to date simultaneously targets both cancer cell survival and gut microbiome restoration. We designed thiazole-based pyruvate kinase M2 (PKM2) inhibitors, hypothesizing that selective modulation may suppress tumor growth while restoring gut microbial balance. 10j selectively inhibited PKM2 in a cell-free assay (0.01 ± 0.0009 μM) and in CRC cells (4.21 ± 0.04 μM), disrupting key pathways driving CRC progression. Remarkably, metagenomic analysis revealed that 10j restored gut microbiota balance. These findings suggest that dual-function anticancer agents, which kill cancer cells while simultaneously restoring gut microbiota, represent an unexplored therapeutic avenue. Thiazole-based PKM2 inhibitors are pioneering this novel strategy in CRC treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203801","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

Beyond Bioisosteres: Impact of Replacing a Benzene Ring with sp3-Rich Three-Dimensional Saturated Bridged Bicyclic Match Pairs on Biotransformation, Metabolic Stability, and Other ADME Profiles. 超越生物同位体：用富含sp3的三维饱和桥联双环配对对取代苯环对生物转化、代谢稳定性和其他ADME谱的影响。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1021/acs.jmedchem.5c01879

Shruti Surendran,Sivashankaran Raju,Naveen Kalyani,Gaurav Saini,Joyson Nandha,Himangshu Bhowmik,Anil Rathod,Shruti Shikha Choubey,Bhuvaneshwaran Anandamoorthy,Sukanta Kumar Sahoo,Yogesh Kumar Gupta,Muthalagu Vetrichelvan,Anuradha Gupta,Salil Desai,Thanga Mariappan,Arvind Mathur,Prakash Ramaseshan Vachaspati,Murugaiah A M Subbaiah

{"title":"Beyond Bioisosteres: Impact of Replacing a Benzene Ring with sp3-Rich Three-Dimensional Saturated Bridged Bicyclic Match Pairs on Biotransformation, Metabolic Stability, and Other ADME Profiles.","authors":"Shruti Surendran,Sivashankaran Raju,Naveen Kalyani,Gaurav Saini,Joyson Nandha,Himangshu Bhowmik,Anil Rathod,Shruti Shikha Choubey,Bhuvaneshwaran Anandamoorthy,Sukanta Kumar Sahoo,Yogesh Kumar Gupta,Muthalagu Vetrichelvan,Anuradha Gupta,Salil Desai,Thanga Mariappan,Arvind Mathur,Prakash Ramaseshan Vachaspati,Murugaiah A M Subbaiah","doi":"10.1021/acs.jmedchem.5c01879","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01879","url":null,"abstract":"The increasing adoption of 3D sp3-hybridized bridged bicyclic moieties as saturated bioisosteres of benzene rings signifies a compelling evolution in modern medicinal chemistry, facilitated by recent synthetic advancements. Inspired by this, we evaluated the metabolic stability and other ADME profiles of various bridged bicyclic systems, comparing them to a monosubstituted benzene counterpart. Our findings indicate that these bicyclic scaffolds enhance metabolic stability, with further notable enhancements achieved by strategic structural modifications, such as fluorine substitution at the bridgehead sp3 carbon or incorporation of an oxygen atom within the bridge. Importantly, metabolite profiling revealed that these analogues effectively mitigate the formation of reactive metabolites, a critical liability of phenyl-containing compounds. Notably, the tested oxabicyclic match pairs demonstrated overall more favorable ADME profiles than the phenyl counterpart. These results collectively underscore the promising potential of bridged bicyclic systems to address key challenges in drug metabolism and ADME properties, thereby offering valuable insights for drug design.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"99 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203805","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

What, This "Base" Is Not a Base? Common Misconceptions about Aqueous Ionization That May Hinder Drug Discovery and Development. 什么，这个“基地”不是基地吗？关于水电离的常见误解可能阻碍药物的发现和开发。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1021/acs.jmedchem.5c01783

Robert Fraczkiewicz

引用次数: 0