Journal of Medicinal Chemistry最新文献_第7页

FAP-Triggered In Situ Self-Assembly of HPQ in Tumors Empowers 131I Internal Radiotherapy fap触发的肿瘤中HPQ的原位自组装增强了131I内部放疗的能力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02605

Jiang Wu,Yan Hu,Guoqiang Zhou,Benqin Xu,Chenhao Liao,Yumin Chen,Peixin Lin,Panpan Chen,Tingyou Li,Feng Wang

{"title":"FAP-Triggered In Situ Self-Assembly of HPQ in Tumors Empowers 131I Internal Radiotherapy","authors":"Jiang Wu,Yan Hu,Guoqiang Zhou,Benqin Xu,Chenhao Liao,Yumin Chen,Peixin Lin,Panpan Chen,Tingyou Li,Feng Wang","doi":"10.1021/acs.jmedchem.6c02605","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02605","url":null,"abstract":"Abstract Fibroblast activating protein (FAP) is specifically overexpressed in malignant tumors. The 2-(2′-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) scaffold exhibits hydrophobicity, aggregation-induced emission (AIE). The responsive probes built on HPQ can undergo in situ activation and self-assembling precipitation, enabling prolonged retention in lesion sites. Herein, a FAP-cleavable Cbz-Gly-Pro-sequence was conjugated to the phenolic hydroxyl of HPQ via a self-immolative linker, with phenol/tyrosine moieties for 131I labeling through aliphatic linkers, affording LWH-1 and LWH-2. LWH-3 further incorporated a tetraphenylethylene moiety, a PEG6-triazole-PEG6 linker, and (D-Tyr)5-NH2. All precursors for radioiodination responded efficiently to FAP, releasing HPQ-OH to generate AIE and illuminating tumors for over 48 h. [131I]LWH-3 showed a 2.76-fold higher molar activity than [131I]LWH-2 and an in vivo half-life of 43.66 min. In PC12-FAP xenografts, [131I]LWH-3 achieved outstanding antitumor efficacy with favorable biosafety. Transcriptomic and metabolomic analyses revealed that internal radiotherapy attenuated tumor metabolic adaptability by modulating fatty acid metabolism-associated networks to impair proliferation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210329","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}

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Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis 发现治疗严重急性胰腺炎的新型STING抑制剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c02889

Famin Zhang,Xinwang Li,Bin Zhu,Junjie Zhao,Cencen Lei,Feilong Zhou,Duo Ma,Xinhua Liu

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Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses n -羟基吲哚-2-羧胺类新型宿主靶向广谱抗病毒药物的研究进展

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01625

Giulia Bononi,Giulia Sibille,Erika Plicanti,Fabio Testori,Giusy L. Fratello,Arianna Maggiora,Iole Mannella,Stefano Sainas,Marta Giorgis,Donatella Boschi,Riccardo Miggiano,Miriana Di Stefano,Lisa Piazza,Carlotta Granchi,Giulio Poli,Tiziano Tuccinardi,Valeria Di Bussolo,Giulia Freer,Mauro Pistello,Davide M. Ferraris,Giorgio Gribaudo,Marco L. Lolli,Filippo Minutolo

{"title":"Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses","authors":"Giulia Bononi,Giulia Sibille,Erika Plicanti,Fabio Testori,Giusy L. Fratello,Arianna Maggiora,Iole Mannella,Stefano Sainas,Marta Giorgis,Donatella Boschi,Riccardo Miggiano,Miriana Di Stefano,Lisa Piazza,Carlotta Granchi,Giulio Poli,Tiziano Tuccinardi,Valeria Di Bussolo,Giulia Freer,Mauro Pistello,Davide M. Ferraris,Giorgio Gribaudo,Marco L. Lolli,Filippo Minutolo","doi":"10.1021/acs.jmedchem.6c01625","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01625","url":null,"abstract":"Endoplasmic reticulum (ER) oxidoreductases are promising targets for host-targeted antiviral agents (HTAs) because of their essential role in protein folding, including the maturation of viral proteins. Human protein disulfide isomerase family member A3 (PDIA3) is involved in the folding of N-glycosylated client proteins, including viral envelope proteins, making it an attractive but underexplored antiviral target. Here, we describe the discovery of a novel N-hydroxyindole-2-carboxamide class of PDIA3 inhibitors, exemplified by compound AV22 (1o), which effectively inhibits PDIA3 activity and exerts broad-spectrum antiviral activity against major human respiratory viruses. Mechanistic studies indicated that AV22 (1o) increased the release of non-infectious coronavirus particles and reduced disulfide bond formation in the coronavirus spike protein, indicating that its antiviral effect stems from interference with PDIA3 activity. This new class of HTAs provides promising leads for drug discovery targeting viral envelope protein maturation vulnerabilities and is suitable for developing new BSAs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152141","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}

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Discovery of a Novel Dual Inhibitor Targeting Tubulin and Histone Deacetylase 8 for Treatment of the Ovarian Cancer 一种新的靶向微管蛋白和组蛋白去乙酰化酶8治疗卵巢癌的双重抑制剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01002

Shaowen Cai,Furui Shi,Jiayi Chen,Min Yu,Zhixian Shi,Hairong Tang,Yang Wang

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Repurposing Approved Chemotherapeutics as Intrinsic Photosensitizers for Single-Molecule Chemophototherapy 重新利用已批准的化疗药物作为单分子化学光敏剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c02353

Giulia Greco,Giulia Giugliano,Alessia Marconi,Paolo Emidio Costantini,Michele Trivini,Giulia Neggiani,Francesca Maffei,Manuele Di Sante,Tainah Dorina Marforio,Alessandro Calza,Manuela Sollazzo,Anna Maria Porcelli,Giuseppe Gasparre,Francesco Zerbetto,Alberto Danielli,Julia Westermayr,Matteo Di Giosia,Carmela Fimognari,Eleonora Turrini,Edoardo Jun Mattioli,Matteo Calvaresi

{"title":"Repurposing Approved Chemotherapeutics as Intrinsic Photosensitizers for Single-Molecule Chemophototherapy","authors":"Giulia Greco,Giulia Giugliano,Alessia Marconi,Paolo Emidio Costantini,Michele Trivini,Giulia Neggiani,Francesca Maffei,Manuele Di Sante,Tainah Dorina Marforio,Alessandro Calza,Manuela Sollazzo,Anna Maria Porcelli,Giuseppe Gasparre,Francesco Zerbetto,Alberto Danielli,Julia Westermayr,Matteo Di Giosia,Carmela Fimognari,Eleonora Turrini,Edoardo Jun Mattioli,Matteo Calvaresi","doi":"10.1021/acs.jmedchem.6c02353","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02353","url":null,"abstract":"Chemophototherapy (CPT), combining chemotherapy and photodynamic therapy (PDT), is a promising strategy to enhance anticancer efficacy while reducing systemic toxicity. Many approved drugs contain chromophoric moieties that absorb visible light, suggesting their potential as intrinsic photosensitizers. Herein, we introduce a single-molecule chemophototherapy (SM-CPT) approach based on computational screening of approved anticancer drugs for repurposing as photosensitizers. A curated library of 238 small-molecule drugs was screened using time-dependent density functional theory to identify compounds with favourable photophysical properties. Fifteen candidates were identified, and mitoxantrone, pixantrone, daunorubicin, and epirubicin were selected for experimental validation. All compounds generated reactive oxygen species upon irradiation and showed enhanced cytotoxicity in breast cancer cell models, with up to an order-of-magnitude reduction in half-maximal inhibitory concentration values. The approach was further validated in ovarian cancer models, including platinum-resistant cells and patient-derived ascites, highlighting SM-CPT as a translationally attractive light-activated cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152168","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}

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Developing a Ferric(III) Agent for Targeted Inhibition of Growth and Metastasis of Triple-Negative Breast Cancer Based on Human Serum Albumin by Chemodynamic Therapy-Driven Synergistic Therapy 基于人血清白蛋白的铁（III）靶向抑制三阴性乳腺癌生长和转移的化学动力学驱动协同疗法

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01103

Wenjuan Li,Shanhe Li,Zhongzhao Li,Gang Xu,Guochao Li,Zhenlei Zhang,Hong Liang,Feng Yang

{"title":"Developing a Ferric(III) Agent for Targeted Inhibition of Growth and Metastasis of Triple-Negative Breast Cancer Based on Human Serum Albumin by Chemodynamic Therapy-Driven Synergistic Therapy","authors":"Wenjuan Li,Shanhe Li,Zhongzhao Li,Gang Xu,Guochao Li,Zhenlei Zhang,Hong Liang,Feng Yang","doi":"10.1021/acs.jmedchem.6c01103","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01103","url":null,"abstract":"Triple-negative breast cancer (TNBC) remains challenging due to its aggressiveness and the lack of targeted therapies. In this study, we proposed designing a ferric (Fe) agent based on human serum albumin (HSA) for chemodynamic therapy-driven synergistic therapy. To this end, we not only optimized a series of Fe(III) compounds to obtain Fe4, which has remarkable toxicity against TNBC cells, but we also constructed the HSA-Fe4 NPs delivery system. Structural analysis revealed that Fe4 binds within the IB subdomain of HSA, with His-146 coordinating the iron center. Importantly, Fe4/HSA-Fe4 NPs significantly suppressed the metastasis and growth of TNBC in vivo. Moreover, we elucidated the mechanisms by which Fe4/HSA-Fe4 NPs inhibited the growth and metastasis of TNBC: inducing Fenton reaction-mediated chemodynamic therapy, inducing ferroptosis, and tri-activating the immune response through the activation of the cGAS-STING pathway, the induction of immunogenic cell death, and the repolarization of M2 macrophages.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152138","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

Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB 抗毒苯并噻吩靶向组氨酸激酶MprB抑制细胞内结核分枝杆菌

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01530

Vladislav Lobanov,Andréanne Lupien,Anthony Vocat,Rajkumar Singh,Alexander Lepioshkin,Natalia Monakhova,Olga Riabova,Maria G. Khrenova,Stewart T. Cole,Vadim Makarov

{"title":"Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB","authors":"Vladislav Lobanov,Andréanne Lupien,Anthony Vocat,Rajkumar Singh,Alexander Lepioshkin,Natalia Monakhova,Olga Riabova,Maria G. Khrenova,Stewart T. Cole,Vadim Makarov","doi":"10.1021/acs.jmedchem.6c01530","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01530","url":null,"abstract":"Pulmonary tuberculosis remains one of the most prevalent and threatening infectious diseases. Classical anti-tubercular therapy targets essential enzymes of the pathogen Mycobacterium tuberculosis (Mtb), thereby suppressing bacterial growth. However, the emergence of drug-resistant strains necessitates alternative therapeutic approaches. Virulence inhibition is a promising strategy that blocks Mtb virulence factors required for survival within host cells. We previously identified a hit compound, BTP15, which protected fibroblasts and THP-1 macrophages from Mtb-induced cell death ex vivo by blocking phagosomal escape through inhibition of the mycobacterial histidine kinase MprB. Due to poor pharmacokinetics, the structure of BTP15 was optimized. New benzothiophene derivatives were screened for MprB inhibition, microsomal stability, toxicity, and ex vivo efficacy in THP-1 and MRC-5 cells. The lead compound, 7a, exhibited favorable pharmacokinetic parameters, showed no toxicity in mice at 250 mg/kg, and prevented Mtb dissemination in an acute mouse model of tuberculosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"59 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152137","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}

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Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades 金鸡纳生物碱衍生铵盐用于长效和感觉选择性神经阻滞

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01940

Yu Deng,Bingbing Xiang,Han Yang,Xudong Luo,Chaoyi Deng,Wensheng Zhang

引用次数: 0

Structure-Based Design of HDAC6 Inhibitors Targeting the L2 Pocket: Modulating Autophagy and Liquid−Liquid Phase Separation in Lung Cancer 靶向L2口袋的HDAC6抑制剂基于结构的设计：调节肺癌自噬和液-液相分离

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c02004

Simona Barone,Abraham Eafa,Ivana Bello,Gessica Filocamo,Alessia Alberico,Emilia Cassese,Anna Guadagni,Heiko Rebmann,Emanuela Cosentino,Juana Goulart Stollmaier,Aubry K. Miller,Vincenzo Summa,Longlong Wang,Elisabetta Panza,David W. Christianson,Margherita Brindisi

{"title":"Structure-Based Design of HDAC6 Inhibitors Targeting the L2 Pocket: Modulating Autophagy and Liquid−Liquid Phase Separation in Lung Cancer","authors":"Simona Barone,Abraham Eafa,Ivana Bello,Gessica Filocamo,Alessia Alberico,Emilia Cassese,Anna Guadagni,Heiko Rebmann,Emanuela Cosentino,Juana Goulart Stollmaier,Aubry K. Miller,Vincenzo Summa,Longlong Wang,Elisabetta Panza,David W. Christianson,Margherita Brindisi","doi":"10.1021/acs.jmedchem.6c02004","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02004","url":null,"abstract":"We herein describe the structure-based design, synthesis and biological evaluation of a new class of histone deacetylase 6 (HDAC6) inhibitors guided by X-ray crystal structures of our previously identified compounds 13-15. X-ray co-crystal structures of second-generation inhibitors 19b (Subseries I) and 20b (Subseries II) within zHDAC6 CD2 confirmed that these compounds behave as highly potent HDAC6 inhibitors with the ability to engage the S531 residue in the L2 loop HDAC6 catalytic domain. Western-blot analysis confirmed the target engagement in cell-based settings, through the increase of acetylated tubulin levels, without significant variation in the histone acetylation status. Compound 20b extensively reduced the viability of A549 cells in both 2- and 3-dimensional cell cultures, through the activation of pro-autophagic pathways. In addition, HDAC6 inhibition impaired the nucleation of stress-granules, confirming the ability of these compounds to modulate liquid−liquid phase separation, an emerging HDAC6-driven hallmark in cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152142","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}

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Rational Design of Near-Infrared Difluoroboron Cyanine Photosensitizers for Lipid Droplet-Targeting Imaging and Tumor Therapy 用于脂滴靶向成像和肿瘤治疗的近红外二氟硼氰光敏剂的合理设计

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01845

Li Chen,Yutong Wang,Jun Yang,Qian Li,Shuming Chen,Yong Wang,Wuyu Mao,Jifa Zhang

{"title":"Rational Design of Near-Infrared Difluoroboron Cyanine Photosensitizers for Lipid Droplet-Targeting Imaging and Tumor Therapy","authors":"Li Chen,Yutong Wang,Jun Yang,Qian Li,Shuming Chen,Yong Wang,Wuyu Mao,Jifa Zhang","doi":"10.1021/acs.jmedchem.6c01845","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01845","url":null,"abstract":"Specifically disrupting lipid droplets (LDs) is an effective strategy for ablating tumor cells through photodynamic therapy (PDT). However, most reported LD probes possess short excitation/emission wavelengths, limiting tissue penetration, and LD-targeted theranostic probes remain underdeveloped. In this work, we first developed a family of near-infrared (NIR) charge-neutral and lipid droplet-targeting cyanine photosensitizers by systematically introducing heavy atoms (Br/I) at different sites of electrically neutral BF2-bridged cyanine (BCy5). These BCy photosensitizers retain the characteristic near-infrared absorption (>650 nm) and high molar extinction coefficients of classical cyanine dyes while exhibiting good singlet oxygen quantum yields. Notably, BCy5-Br1−BCy5-Br3 nanoparticles with high LD specificity exhibit significant PDT efficacy at submicromolar concentrations and, by inducing oxidative stress and lipid peroxidation (LPO) accumulation, concurrently trigger apoptosis and ferroptosis, effectively suppressing melanoma growth in vivo. This work provides vital insights into design principles and transformation of LD-targeting NIR cyanine photosensitizers for cancer PDT.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152135","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