Journal of Medicinal Chemistry最新文献_第3页

Redox-Inactive Terpyridine Zn(II)-Azide Complexes for Photodynamic and Photoactivatable Chemotherapy. 用于光动力和光活化化疗的氧化还原活性三联吡啶锌（II）叠氮化物配合物。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-29 DOI: 10.1021/acs.jmedchem.5c01612

Tejal Dixit,Kartikay Tyagi,V Venkatesh

{"title":"Redox-Inactive Terpyridine Zn(II)-Azide Complexes for Photodynamic and Photoactivatable Chemotherapy.","authors":"Tejal Dixit,Kartikay Tyagi,V Venkatesh","doi":"10.1021/acs.jmedchem.5c01612","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01612","url":null,"abstract":"The rational design of metal complexes exhibiting both photodynamic therapy (PDT) and photoactivatable chemotherapy (PACT) remains a significant challenge in the phototherapeutic regimen. Herein, we developed a series of terpyridine zinc(II)-azide complexes; among them, lead complex Tpatpy@ZnN3 shows both type I and type II PDT, along with the photorelease of azidyl radicals. The Tpatpy@ZnN3 complex targets mitochondria; upon blue light activation (456 nm), it generates singlet oxygen (1O2), hydroxyl radical (•OH), and azidyl radical (N3•). The produced reactive oxygen and nitrogen species induce oxidative stress, ultimately leading to mitochondrial-mediated cellular apoptosis. The complex demonstrated significant efficacy in both two-dimensional (2D) cancer cells and three-dimensional (3D) multicellular tumor spheroids. Notably, the zinc(II) complex is biocompatible, cost-effective, and redox-inactive, exhibiting negligible dark toxicity. This study highlights the efficacy of Tpatpy@ZnN3 for synergistic and enhanced therapeutic potential with spatial and temporal precision, paving the way for the development of photoactivatable zinc complexes for cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"91 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189471","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

De Novo Design of Mirror-Image Dimeric Antimicrobial Peptides with Low Drug Resistance and In Vivo Efficacy. 具有低耐药性和体内有效性的镜像二聚体抗菌肽的从头设计。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-29 DOI: 10.1021/acs.jmedchem.5c01375

Jingying Zhang,Anqi Chu,Ping Yang,Xu Ouyang,Beibei Li,Wenbo Mao,Xiaoyan Wu,Chao Zhong,Sanhu Gou,Yun Zhang,Hui Liu,Jingman Ni

{"title":"De Novo Design of Mirror-Image Dimeric Antimicrobial Peptides with Low Drug Resistance and In Vivo Efficacy.","authors":"Jingying Zhang,Anqi Chu,Ping Yang,Xu Ouyang,Beibei Li,Wenbo Mao,Xiaoyan Wu,Chao Zhong,Sanhu Gou,Yun Zhang,Hui Liu,Jingman Ni","doi":"10.1021/acs.jmedchem.5c01375","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01375","url":null,"abstract":"Dimerization and mirror-image modification are effective strategies for enhancing the antimicrobial activity and stability of antimicrobial peptides (AMPs). However, mirror-image dimeric AMPs, characterized by their mirror-image amino acid sequences and mirror-image stereocenters within a single peptide, have been rarely reported. In this study, 19 mirror-image dimeric AMPs and 2 all d-/l-type AMPs are designed and synthesized to investigate their structure-activity relationships. Peptides with YYYXXxxyyy or yyyxxXXYYY sequences (X/Y represents cationic/hydrophobic residues, x/y denotes d-type residues) possess favorable bacterial selectivity. The superior peptide M-WL-D/L exhibits potent activity against multidrug-resistant bacteria, a low propensity for drug resistance, favorable stability, robust membrane disruption, high DNA affinity, and immunoregulatory activity. Notably, M-WL-D/L demonstrates in vivo half-lives of 22.4 min (5 mg/kg) and 20.7 min (10 mg/kg), along with effective in vivo efficacy and satisfactory safety. This innovative AMP design strategy, with M-WL-D/L as a standout candidate, offers a promising avenue for combating multidrug-resistant bacteria.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189473","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

Correction to “Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads” 对“铼(V)配合物作为半胱氨酸靶向配位共价弹头”的修正

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-29 DOI: 10.1021/acs.jmedchem.5c02640

Johannes Karges, Seth M. Cohen

引用次数: 0

Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant. 扩展酰基重氮亲电试剂作为KRAS （G12D）突变体共价靶向可调战斗部的化学性质。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-28 DOI: 10.1021/acs.jmedchem.5c01365

Tianbai Shuai,Rong Zhang,Zihang Yuan,Mingya Zhang,Zhongjiao Fan,Xiaoxue Ruan,Zhiyuan Qi,Wenhao Xie,Ping Liu,Motonari Uesugi,Qing Li,Zhibei Qu,Minjia Tan,Hua Su,Lu Zhou

引用次数: 0

Fluorinated Modification as a Simple Strategy That Effectively Enhances the Stability and Activity of Antimicrobial Peptides. 氟化修饰是一种有效提高抗菌肽稳定性和活性的简单策略。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-28 DOI: 10.1021/acs.jmedchem.5c00922

Xu Ouyang,Liru Yuan,Tingting Yang,Qingyang Xu,Beibei Li,Jingying Zhang,Jie Liu,Lanqing Hu,Zufang Ba,Yao Liu,Yu Wang,Zhongwei Yu,Pengyi Yan,Bingqian Ren,Xueting Liu,Chao Zhong,Hui Liu,Yun Zhang,Sanhu Gou,Jingman Ni

{"title":"Fluorinated Modification as a Simple Strategy That Effectively Enhances the Stability and Activity of Antimicrobial Peptides.","authors":"Xu Ouyang,Liru Yuan,Tingting Yang,Qingyang Xu,Beibei Li,Jingying Zhang,Jie Liu,Lanqing Hu,Zufang Ba,Yao Liu,Yu Wang,Zhongwei Yu,Pengyi Yan,Bingqian Ren,Xueting Liu,Chao Zhong,Hui Liu,Yun Zhang,Sanhu Gou,Jingman Ni","doi":"10.1021/acs.jmedchem.5c00922","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00922","url":null,"abstract":"Antimicrobial peptides (AMPs) are promising antibacterial agents; however, their issues, such as proteolytic degradation and nonspecific toxicity, hinder their clinical application. WK2 (GWWKKWWKKI-NH2) is an AMP with a good antimicrobial performance, which was screened out in our previous study. However, it has poor stability. In this study, the sequence of WK2 was modified with unnatural amino acids based on predicting its proteolytic cleavage sites by computer. The enzymatic hydrolysis stability, antimicrobial activity, and cytotoxicity of the new WK2 analogs were systematically evaluated, and their structure-activity relationships were studied. Compared with WK2, its fluoropeptide analogue, FuK, exhibits excellent antibacterial properties. In particular, the serum half-life of FuK exceeds 1440 min, which is at least 6.4-fold that of WK2. In vivo, FuK demonstrated excellent safety and therapeutic efficacy. In conclusion, fluorination modification may be a rather promising strategy that can effectively enhance the antimicrobial properties and stability of the new AMPs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182566","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

The Pathological Nexus and Multipronged Approaches to Mitigate Ferroptosis and Alzheimer's Disease. 病理联系和多管齐下的方法减轻铁下垂和阿尔茨海默病。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-26 DOI: 10.1021/acs.jmedchem.5c00917

Hariharan Moorthy,Shreyasri Sain,Dikshaa Padhi,Thimmaiah Govindaraju

{"title":"The Pathological Nexus and Multipronged Approaches to Mitigate Ferroptosis and Alzheimer's Disease.","authors":"Hariharan Moorthy,Shreyasri Sain,Dikshaa Padhi,Thimmaiah Govindaraju","doi":"10.1021/acs.jmedchem.5c00917","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00917","url":null,"abstract":"Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder and a leading cause of dementia. Although the amyloid cascade is a defining feature of AD pathology, the precise mechanisms underlying neurodegeneration remain unclear, and current therapeutics targeting this have shown limited efficacy. Emerging evidence implicates ferroptosis, an iron-dependent, lipid peroxidation (LPO)-driven form of regulated cell death, as a contributing factor in AD-related neuronal loss. Core biomarkers of ferroptosis, including iron dyshomeostasis, LPO, and reduced antioxidant capacity, closely align with hallmark features of AD suggesting a pathological nexus further supported by clinical evidence. While the use of LPO inhibitors and iron chelators has shown promising outcomes, there remains a significant gap in targeting key ferroptosis regulators, such as GPX4 and FSP1, which hold strong therapeutic potential in AD. This perspective explores their pathological interplay and offers strategic insights for the development of hybrid multifunctional therapeutic molecules to synergistically target these interconnected pathways.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140136","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

HSP90 Mediates Targeted Degradation of Nonclient Protein PARP1 for Breast Cancer Treatment HSP90介导非客户蛋白PARP1靶向降解用于乳腺癌治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-26 DOI: 10.1021/acs.jmedchem.5c00409

Wei Liu, Jianfeng Liu, Huangliang Shu, Lixiao Zhang, Xingyu Yin, Xiaoli Xu, Qidong You, Lei Wang

{"title":"HSP90 Mediates Targeted Degradation of Nonclient Protein PARP1 for Breast Cancer Treatment","authors":"Wei Liu, Jianfeng Liu, Huangliang Shu, Lixiao Zhang, Xingyu Yin, Xiaoli Xu, Qidong You, Lei Wang","doi":"10.1021/acs.jmedchem.5c00409","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00409","url":null,"abstract":"Heat shock protein 90 (HSP90) has been developed as an effector in mediating targeted protein degradation (TPD), representing a novel strategy in TPD drug design. The majority of reported cases of HSP90-mediated degradation targeted HSP90 client proteins, including BRD4-CHAMPs, CDK4/6-HEMTACs, and GPX4-HIM-PROTACs. However, HSP90 ATPase inhibitor was used to design the above molecules, which might cause nonspecific degradation of other client proteins. In this study, we sought to broaden the scope of HSP90-mediated proteolysis-targeting chimeras (HSPTACs) from client protein degradation to include nonclient protein degradation. Herein, we induced unnatural interactions between poly(ADP-ribose) polymerase-1 (PARP1), a nonclient protein of HSP90, and HSP90 by bridging them with a small molecule (DDO3602). DDO3602 effectively induced PARP1 degradation through a multi-E3 ubiquitin ligase-mediated degradation pathway. In general, this study demonstrates that DDO3602 can degrade the HSP90 nonclient protein PARP1 through the ubiquitin-proteasome pathway and exhibits tumor-selective pharmacokinetics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141051","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

Cellular Potency Optimization of Novel Heme-Binding Imidazo[5,1-b]thiazoles, Imidazo[1,5-a]pyridines and Pyrazines as Potent IDO1 Inhibitors Devoid of Cytochrome P450 Inhibition. 新型血红素结合咪唑[5,1-b]噻唑、咪唑[1,5-a]吡啶和吡嗪作为不抑制细胞色素P450的IDO1抑制剂的细胞效价优化

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-26 DOI: 10.1021/acs.jmedchem.5c01067

Sylvaine Cren,Carina Lotz-Jenne,Thierry Kimmerlin,Julien Pothier,Philippe Risch,Aengus Mac Sweeney,Christoph Joesch,Laetitia Pouzol,Alexia Chavanton-Arpel,Christoph Boss

{"title":"Cellular Potency Optimization of Novel Heme-Binding Imidazo[5,1-b]thiazoles, Imidazo[1,5-a]pyridines and Pyrazines as Potent IDO1 Inhibitors Devoid of Cytochrome P450 Inhibition.","authors":"Sylvaine Cren,Carina Lotz-Jenne,Thierry Kimmerlin,Julien Pothier,Philippe Risch,Aengus Mac Sweeney,Christoph Joesch,Laetitia Pouzol,Alexia Chavanton-Arpel,Christoph Boss","doi":"10.1021/acs.jmedchem.5c01067","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01067","url":null,"abstract":"Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are key enzymes in the kynurenine pathway of the catabolism of the essential amino acid tryptophan. Both enzymes actively contribute to the immunosuppressive microenvironment in many types of cancer. Selective or dual inhibition of these enzymes could, therefore, be beneficial in combination with other immunotherapies such as immune-checkpoint therapy. In a fragment-based approach, we optimized fragment 3 into a series of potent imidazo[5,1-b]thiazole, imidazo[1,5-a]pyridine and pyrazine IDO1 inhibitors. The introduction of the triazole side chain resulted in a reduced enzyme-to-cell potency shift for IDO1 inhibition, albeit at the expense of TDO2 potency, and allowed the discovery of potent and cellular active IDO1 inhibitors. Moreover, despite the propensity of the imidazole motif to inhibit cytochrome P450 enzymes (CYP), we were able to discover potent IDO1 inhibitors devoid of CYP inhibition. Imidazo[1,5-a]pyrazine (R)-100 has an overall suitable profile, which warrants further investigation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"324 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140135","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 an Orally Active PDE1 Inhibitor for Disease-Modifying Treatment of Postmenopausal Osteoporosis via Dual Anabolic-Antiresorptive Mechanisms. 口服活性PDE1抑制剂通过双重合成代谢-抗吸收机制改善绝经后骨质疏松症的治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-26 DOI: 10.1021/acs.jmedchem.5c01736

Farman M Abbasi,Konica Porwal,Subhashis Pal,Shivani Sharma,Sreyanko Sadhukhan,Swati Rajput,Chirag Kulkarni,Shubham K Talware,Mohammad I Siddiqi,Divya Chauhan,Jiaur R Gayen,Naibedya Chattopadhyay,Sanjay Batra

{"title":"Discovery of an Orally Active PDE1 Inhibitor for Disease-Modifying Treatment of Postmenopausal Osteoporosis via Dual Anabolic-Antiresorptive Mechanisms.","authors":"Farman M Abbasi,Konica Porwal,Subhashis Pal,Shivani Sharma,Sreyanko Sadhukhan,Swati Rajput,Chirag Kulkarni,Shubham K Talware,Mohammad I Siddiqi,Divya Chauhan,Jiaur R Gayen,Naibedya Chattopadhyay,Sanjay Batra","doi":"10.1021/acs.jmedchem.5c01736","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01736","url":null,"abstract":"Postmenopausal osteoporosis (PMO) is characterized by an imbalance in bone remodeling with increased osteoclast and decreased osteoblast activity, leading to bone loss and higher fracture risk. Current treatments, such as teriparatide, boost bone formation but also elevate resorption, limiting their long-term effectiveness. We discovered 3-butyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5cc), an orally active phosphodiesterase-1 (PDE1) inhibitor aimed at restoring this balance. 5cc enhances osteoblast differentiation assessed by increased alkaline phosphatase activity, Runx2 expression, and mineralized nodule formation. Additionally, it inhibited osteoclastogenesis by suppressing the RANKL/OPG ratio, modulating Eph-Ephrin signaling, and attenuating IL-1β-induced ROS and NF-κB activation in vitro. In ovariectomized mice, 5cc administration (5 mg/kg) improved the trabecular microarchitecture, bone mineral density, and strength, at levels comparable to teriparatide, while significantly reducing bone resorption markers. With 13.57% oral bioavailability and selectivity for PDE1A1 (32% inhibition at 500 nM), 5cc offers an innovative therapeutic candidate for PMO with a dual anabolic-antiresorptive profile and oral efficacy, warranting further clinical development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140151","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

Correction to “Development and Evaluation of Indole-Based Phospholipase D Inhibitors for Lung Cancer Immunotherapy” 对“吲哚类磷脂酶D抑制剂用于肺癌免疫治疗的开发与评价”的更正

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-26 DOI: 10.1021/acs.jmedchem.5c02366

Doona Song, Seong Hun Lim, Yeji Kim, Hyesung Lee, Taehyun Kim, Hocheol Lim, Do Sik Min, Gyoonhee Han

引用次数: 0