Journal of Medicinal Chemistry最新文献

{"title":"Synthesis and Preclinical Evaluation of Novel 99mTc-Labeled FR-Targeting Agents with Satisfactory Imaging Contrast and Reduced Renal Uptake","authors":"Junhong Feng, Qianna Wang, Guangxing Yin, Yuhao Jiang, Qing Ruan, Peiwen Han, Qingna Xiao, Dajie Ding, Zuojie Li, Jin Du, Junbo Zhang","doi":"10.1021/acs.jmedchem.4c02932","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02932","url":null,"abstract":"The folate receptor is overexpressed in a variety of epithelial-derived malignant cells. Several folate-based tracers have shown the ability to target FR, but excessive renal uptake is a general concern. To decrease renal uptake and achieve high target-to-nontarget ratios, two folate derivatives (DProFA and DAlaFA) were designed and synthesized. Eight complexes with high labeling yields and good in vitro stability were obtained by radiolabeling with technetium-99m and different coligands. The results of both in vitro cell and in vivo normal mice biodistribution studies demonstrated specific binding of eight complexes to the FR. Among them, [^99mTc]Tc-DProFA-L1 exhibited lower off-target uptake and high tumor uptake in tumor-bearing mice, and significant inhibition in the biodistribution and SPECT/CT imaging study. The lower renal uptake of [^99mTc]Tc-DProFA-L1 may prevent irradiation damage to the kidney. Consequently, [^99mTc]Tc-DProFA-L1 is a highly promising candidate probe for the diagnosis of epithelial tumors in clinical nuclear medicine.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462701","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}

{"title":"Redefining Antifungal Treatment: The Innovation of Metal-Based Compounds","authors":"Joana Cardoso, Eugénia Pinto, Emília Sousa, Diana I. S. P. Resende","doi":"10.1021/acs.jmedchem.4c02084","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02084","url":null,"abstract":"Fungal infections are a significant contributor to global morbidity and mortality, particularly among immunocompromised patients. With the increasing prevalence of drug-resistant strains, it has become imperative to identify alternative approaches. Metal ion coordination enhances drug efficacy through novel modes of action and may hinder resistance mechanisms. This article aims to identify gaps in the current metal-based antifungal therapy to guide research directions and facilitate drug development. Relevant metal complexes, together with their ligands, have been categorized according to their metal coordination and their activities highlighted. Most examples reported were found to be more effective against drug-resistant strains than non-coordinated ligands, thus establishing the importance of metal ion and co-ligand(s) nature, the influence of electron-withdrawing substituents on structure–activity relationships, and the unique structural features of Schiff bases. Although still at the preclinical phase, the <i>in vitro</i> efficacy of these examples suggests that metal-based drugs may represent a promising approach to overcoming antifungal resistance.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"50 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462680","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}

{"title":"Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy","authors":"Jie He, Xiaoyu Ma, Jia Sun, Manman Chen, Lan Xu, Zilan Song, Chunyong Ding, Linghua Meng, Ao Zhang","doi":"10.1021/acs.jmedchem.4c03207","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03207","url":null,"abstract":"ENPP1, a transmembrane glycoprotein overexpressed in various cancers, has become a promising target for tumor immunotherapy. Several ENPP1 inhibitors have been reported, but only a few have been validated <i>in vivo</i>. Herein, based on the reported inhibitors <b>3</b> and <b>6</b>, we carried out a structural optimization by designing a variety of 8-methoxyquinazoline and its equivalent 8-methoxy-3-cyano-quinoline derivatives featuring bridged- or spirobicycles as the linker. Compound <b>30</b> was identified as a promising ENPP1 inhibitor. This compound exhibited IC₅₀ values of 8.05 nM against ENPP1 and 1.53 nM in MDA-MB-231 cells with no significant inhibitory effects against both hERG and a panel of 97 kinases. It effectively activated the intracellular STING pathway by inhibiting cGAMP degradation. In the murine CT-26 tumor model, <b>30</b> inhibited tumor growth with increased immune cell infiltration in the tumor microenvironment and enhanced type I interferon responses. Meanwhile, compound <b>30</b> synergically enhanced the antitumor efficacy of anti-PD-L1 antibody.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452028","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}

{"title":"Structure and Dynamics of Macrophage Infectivity Potentiator Proteins from Pathogenic Bacteria and Protozoans Bound to Fluorinated Pipecolic Acid Inhibitors","authors":"Victor Hugo Pérez Carrillo, Jacob J. Whittaker, Christoph Wiedemann, Jean-Martin Harder, Theresa Lohr, Anil K. Jamithireddy, Marina Dajka, Benedikt Goretzki, Benesh Joseph, Albert Guskov, Nicholas J. Harmer, Ulrike Holzgrabe, Ute A. Hellmich","doi":"10.1021/acs.jmedchem.5c00134","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00134","url":null,"abstract":"Macrophage infectivity potentiator (MIP) proteins, found in pro- and eukaryotic pathogens, influence microbial virulence, host cell infection, pathogen replication, and dissemination. MIPs share an FKBP (FK506 binding protein)-like prolyl-<i>cis/trans</i>-isomerase domain, making them attractive targets for inhibitor development. We determined high-resolution crystal structures of <i>Burkholderia pseudomallei</i> and <i>Trypanosoma cruzi</i> MIPs in complex with fluorinated pipecolic acid inhibitors. The inhibitor binding profiles in solution were compared across <i>B. pseudomallei</i>, <i>T. cruzi</i>, and <i>Legionella pneumophila</i> MIPs using ¹H, ¹⁵N, and ¹⁹F NMR spectroscopy. Demonstrating the versatility of fluorinated ligands for characterizing inhibitor complexes, ¹⁹F NMR spectroscopy identified differences in ligand binding dynamics across MIPs. EPR spectroscopy and SAXS further revealed inhibitor-induced global structural changes in homodimeric <i>L. pneumophila</i> MIP. This study demonstrates the importance of integrating diverse methods to probe protein dynamics and provides a foundation for optimizing MIP-targeted inhibitors in this structurally conserved yet dynamically variable protein family.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452030","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}

{"title":"Chemoproteomic Profiling of a Carbon-Stabilized Gold(III) Macrocycle Reveals Cellular Engagement with HMOX2","authors":"Sailajah Gukathasan, Chibuzor Olelewe, Libby Ratliff, Jong H. Kim, Alyson M. Ackerman, J. Robert McCorkle, Sean Parkin, Gunnar F. Kwakye, Jill M. Kolesar, Samuel G. Awuah","doi":"10.1021/acs.jmedchem.4c02952","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02952","url":null,"abstract":"In this work, we discovered a novel organometallic gold(III) macrocycle, <b>Au-Mac1,</b> that demonstrates anticancer potency in a panel of triple-negative breast cancer cells (TNBC), and based on this complex, a biotinylated-Au-Mac1 probe was designed for target identification via chemoproteomics, which uncovered the engagement of HMOX2 of the heme-energy metabolism pathway. Using orthogonal chemical biology and molecular biology approaches, including immunoblotting, flow cytometry, and cellular thermal shift assays, it was confirmed that <b>Au-Mac1</b> engages HMOX2 in cells. Downstream effects of <b>Au-Mac1</b> on the depletion of mitochondrial membrane proteins and bioenergetics point to the potential role of HMOX2 in cancer. Importantly, <b>Au-Mac1</b> inhibits in vivo tumor growth of metastatic breast tumor-bearing mice. We believe that this approach is clinically relevant in network-oriented drug discovery. To the best of our knowledge, <b>Au-Mac1</b> is the first gold complex that targets HMOX2 to elicit an anticancer effect.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"65 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462705","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}

{"title":"Discovery of a Novel EF24 Analogue-Conjugated Pt(IV) Complex as Multi-Target Pt(IV) Prodrugs Aims to Enhance Anticancer Activity and Overcome Cisplatin Resistance","authors":"Meng Wang, Guimei Li, Nan Xu, Lang Wang, Jinyuan Cai, Rizhen Huang, Yong Yang, Guiping Chen, Zhikun Liu, Ye Zhang, Hengshan Wang, Xiaochao Huang","doi":"10.1021/acs.jmedchem.4c02840","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02840","url":null,"abstract":"Acquired resistance in cancer remains a significant challenge in oncology, posing obstacles to the efficacy of diverse therapeutic approaches. The nuclear factor-kappa B (NF-κB) signaling pathway plays an important role in the development of drug resistance in tumor cells. Herein, we employed NF-κB inhibitors and cisplatin to synthesize multitarget Pt(IV) antitumor prodrugs. Among them, the antiproliferation activity of complex <b>8</b> demonstrated a remarkable 146.92-time increase compared to cisplatin against A549/CDDP cells. Moreover, complex <b>8</b> could effectively induce DNA damage, promote ROS generation, induce autophagy, trigger the mitochondrial apoptosis pathway, and suppress cell proliferation through the NF-κB signaling pathway. Furthermore, complex <b>8</b> effectively downregulated the levels of VEGF and HIF-1α and exerted antiproliferative activity through the PI3K/AKT and STAT-3 pathway in A549/CDDP cells. Interestingly, complex <b>8</b> showed a superior in vivo antitumor activity than cisplatin, <b>5a</b>, or their combination, suggesting its potential as a promising candidate for further drug development in lung cancer treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452026","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}

{"title":"Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy","authors":"Zhihao Hu, Shuqing Li, Haiqi He, Wanyi Pan, Ting Liu, Hailiu Liang, Congcong Xu, Benyan Lu, Chengpeng Tao, Zetao Qi, Binbin Cheng, Ying Hu, Feng Jiang, Jianjun Chen, Xiaopeng Peng","doi":"10.1021/acs.jmedchem.4c02510","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02510","url":null,"abstract":"A series of novel PD-L1/HDAC6 dual inhibitors were designed and synthesized, and compound <b>HP29</b> was identified as the most potent candidate, which demonstrated excellent and selective HDAC6 inhibitory activity (IC₅₀ = 78 nM, SI &gt; 1282), and high anti-PD-1/PD-L1 activity (IC₅₀ = 26.8 nM). Further studies showed that <b>HP29</b> could bind with high affinity to PD-L1 and HDAC6 protein. Furthermore, <b>HP29</b> possessed favorable <i>in vivo</i> pharmacokinetic properties, such as decent oral bioavailability (<i>F</i> = 15.3%). Moreover, <b>HP29</b> exhibited significant <i>in vivo</i> antitumor efficacy in a melanoma tumor model with a greater tumor growth inhibition (TGI) (65.5%) than that of NP19 (43.2%), ACY-1215 (45.6%), and the combination group (53.9%). Mechanistically, the percentages of tumor-infiltrating lymphocytes (TILs) in the <b>HP29</b>-treated tumor tissues were significantly higher than the combination group or PD-L1 inhibitor monotherapy group, suggesting potential synergistic antitumor immune effects. Collectively, <b>HP29</b> represents a novel PD-L1/HDAC6 dual inhibitor deserving further investigation as a potential cancer immunomodulating agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462707","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}

{"title":"ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma.","authors":"Morena Miciaccia, Olga Maria Baldelli, Cosimo G Fortuna, Gianfranco Cavallaro, Domenico Armenise, Anselma Liturri, Savina Ferorelli, Denise Muñoz, Alessandro Bonifazi, Francesca Rizzo, Antonella Cormio, Silvana Filieri, Giuseppe Micalizzi, Paola Dugo, Luigi Mondello, Anna Maria Sardanelli, Francesco Bruni, Paola Loguercio Polosa, Maria Grazia Perrone, Antonio Scilimati","doi":"10.1021/acs.jmedchem.4c01723","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01723","url":null,"abstract":"<p><p>Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease <i>h</i>ClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as <i>h</i>ClpP activators. Among the tested compounds, we have identified <b>36</b> (THX6) that shows a strong <i>h</i>ClpP activation (EC₅₀ = 1.18 μM) and good cytotoxicity in <b>ONC201</b>-resistant cells (IC₅₀ = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with <b>36</b> (THX6) causes a change in levels of fatty acids (PUFAs, MUFAs, and SFAs) compared to untreated cells and dysregulates the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy that lead to a global collapse of mitochondrial integrity and function suggesting this as the mechanism through which <b>36</b> (THX6) accomplishes its antitumor activity in DIPG cell lines.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456239","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}

{"title":"Mn-Specific Recognition of Guanidine Drives Selective Inhibition of Complex I","authors":"Fei Cai, Jinrong Dong, Peng Xie, Hanlong He, Huiyi Yao, Junxian Guo, Zhibo Yan, Li Ma, Tianfeng Chen","doi":"10.1021/acs.jmedchem.4c02904","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02904","url":null,"abstract":"Developing structurally well-defined targeted drugs is an effective way to enhance the chemotherapy efficacy. Herein, a target mitochondrial complex I (complex I) inhibitor was developed for the key methylation site ARG-85 in the key subunit NDUFS2. Based on the unique :NH═C– group of guanidyl and the surrounding environment of ARG-85, the macrocyclic and bulky manganese porphyrin complex [Mn^III(TTPPC^2–)]⁺ was selected to insert into the gap of NDUFS2. Experimental and computational analyses revealed that the planar π system of the TTPPC^2– ligand and the rotatable benzene ring stably bind between the :NH═C– group of ARG-85 and the manganese metal center, a medium-strong Lewis acid. The Mn-specific recognition of guanidine drives the selective inhibition of complex I activity. Further, Mn^III(TTPPC^2–)]⁺ was modified into targeted nanoformulation Mn NPs. In vitro and in vivo experiments confirmed the efficient and mechanism inhibition of complex I activity, offering a novel strategy for targeted drug development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"50 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452027","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}

{"title":"Drug Discovery and Development Faces an Ominous Future from NIH Indirect Costs Rate Cuts","authors":"David E. Heppner","doi":"10.1021/acs.jmedchem.5c00444","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00444","url":null,"abstract":"On February 7, 2025, the Office of the Director of the National Institutes of Health (NIH) issued a Supplemental Guidance to the 2024 NIH Grants Policy Statement, stating: “For all existing grants to [Institutions of Higher Education], retroactive to the date of issuance of this Supplemental Guidance, award recipients are subject to a 15 percent indirect cost rate.” (1) This reduction in the indirect cost (IDC) rate is a considerable cut in financial support for critical overhead and administrative expenses that are essential for health research. Specifically, IDCs are used for facilities such as laboratory space, scientific instruments, research computing infrastructure, safety and regulatory compliance, research core operations, and support staff. They also play a crucial role in sustaining research institutions, and such drastic cuts could lead to the loss of hundreds of millions of dollars for NIH-funded institutions. The implications are profound, threatening to disrupt a wide spectrum of biomedical research, from basic laboratory investigations to clinical trials. Furthermore, the abrupt nature of these cuts leaves institutions with little time to adjust, placing them in immediate financial distress. The medicinal chemistry community, in particular, will face significant setbacks. NIH-funded academic institutions serve as hubs for early stage drug discovery research, identifying novel drug targets and pioneering new chemical entities that may ultimately become transformative therapeutics. The pathway from discovery to market often depends on academic institutions partnering with industry collaborations that facilitate clinical trials and the path toward regulatory approval showing how these cuts will have impacts beyond. While the full impact of these IDC rate reductions remains uncertain, it is evident that they will slow the drug development pipeline, increasing both the time and difficulty of bringing new medicines to patients. At this juncture, it remains unclear how best to navigate these policy changes, despite lawsuits filed and a temporary restraining order. (2,3) Previous funding decisions have already contributed to widespread uncertainty, and further budgetary constraints are likely to exacerbate these challenges. However, drug discovery has long been recognized as a “team sport”, (4) bringing people together in a singular, multidisciplinary workforce dedicated to translating fundamental research into life-changing treatments. In response to these financial constraints, our research community must advocate for resilient support of biomedical research. This includes securing the necessary funding to promote groundbreaking science and fostering the next generation of scientists through robust educational and training programs. Now, more than ever, we must be united to ensure that scientific progress continues unimpeded and that the discovery and development of life-saving therapies remain a national priority. D.E.H. acknowledges ge","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452067","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}