Journal of Medicinal Chemistry最新文献_第2页

Design, Synthesis, and Biological Evaluation of 2-Arylaminopyrimidine Derivatives as Dual Cathepsin L and JAK Inhibitors for the Treatment of Acute Lung Injury

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-19 DOI: 10.1021/acs.jmedchem.4c02030

Chunwei Shen, Zhengtong Mao, Tianpeng Chen, Yingying Wei, Tao Zhou, Ningyuan Zhong, Gaoyang Zhu, Qiwen Shi, Zheyu Xie, Huajun Zhao, Xingxian Zhang

{"title":"Design, Synthesis, and Biological Evaluation of 2-Arylaminopyrimidine Derivatives as Dual Cathepsin L and JAK Inhibitors for the Treatment of Acute Lung Injury","authors":"Chunwei Shen, Zhengtong Mao, Tianpeng Chen, Yingying Wei, Tao Zhou, Ningyuan Zhong, Gaoyang Zhu, Qiwen Shi, Zheyu Xie, Huajun Zhao, Xingxian Zhang","doi":"10.1021/acs.jmedchem.4c02030","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02030","url":null,"abstract":"Acute lung injury (ALI) is a disease characterized by pulmonary inflammation, blood barrier functional disorder, and hypoxemia. Herein, a series of 2-aminopyrimidine derivatives were synthesized. Most of them exhibited inhibitory effects on inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Compound A8 displayed an excellent anti-inflammatory activity, achieving inhibition rates of 83% for IL-6 and 85% for IL-8. Besides, A8 has a strong binding affinity to CTSL and a good inhibitory activity on JAKs. Western blot analysis indicated that compound A8 strongly blocked the maturation of CTSL and the phosphorylation of p-38, p-65, and STATs, thereby repressing the activation of the MAPK, NF-κB, and JAK/STAT signaling pathway. Moreover, animal experiments showed that A8 played a protective and therapeutic role in ALI in mice, validating its potential as a treatment for ALI.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849172","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

Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2) Inhibitors Using a Virtual Screening Approach

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-19 DOI: 10.1021/acs.jmedchem.4c01884

Lucas G. Viviani, Thais S. Iijima, Erika Piccirillo, Leandro Rezende, Thiago G. P. Alegria, Luis Eduardo S. Netto, Antonia T.-do Amaral, Sayuri Miyamoto

{"title":"Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2) Inhibitors Using a Virtual Screening Approach","authors":"Lucas G. Viviani, Thais S. Iijima, Erika Piccirillo, Leandro Rezende, Thiago G. P. Alegria, Luis Eduardo S. Netto, Antonia T.-do Amaral, Sayuri Miyamoto","doi":"10.1021/acs.jmedchem.4c01884","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01884","url":null,"abstract":"The human 15-lipoxygenase-2 (h15-LOX-2) catalyzes mainly the regio- and stereospecific oxygenation of arachidonate to its corresponding hydroperoxide (15(S)-HpETE). h15-LOX-2 is implicated in the biosynthesis of inflammatory lipid mediators and plays a role in the development of atherosclerotic plaques, but it is still underexploited as a drug target. Here, to search for novel h15-LOX-2 inhibitors, we used a virtual screening (VS) approach consisting of shape-based matching, two-dimensional (2D) structural “dissimilarity”, docking, and visual inspection filters, which were applied to a “curated” ZINC database (∼8 × 106 compounds). The VS was experimentally validated, and six micromolar-range inhibitors were identified among 13 tested compounds (46.2%). The Ki values could be determined for two inhibitors, compounds 10 (Ki = 16.4 ± 8.1 μM) and 13 (Ki = 15.1 ± 7.6 μM), which showed a mixed-type mechanism of inhibition. Overall, the identified inhibitors fulfill drug-like criteria and are structurally novel compared with known h15-LOX-2 inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"261 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858179","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

Fluorinated Coumarin Derivatives as Selective PET Tracer for MAO-B Imaging

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-19 DOI: 10.1021/acs.jmedchem.4c01952

Nan Wu, Xiaojun Zhang, Yuying Li, Jinming Zhang, Mengchao Cui

引用次数: 0

Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-18 DOI: 10.1021/acs.jmedchem.4c01865

Anna M. Schoepf, Maximilian Gebhart, Martin Federspiel, Isabel Heidegger, Martin Puhr, Madlen Hotze, Marcel Kwiatkowski, Andreas Pircher, Dominik Wolf, Sieghart Sopper, Ronald Gust, Stefan Salcher

{"title":"Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives","authors":"Anna M. Schoepf, Maximilian Gebhart, Martin Federspiel, Isabel Heidegger, Martin Puhr, Madlen Hotze, Marcel Kwiatkowski, Andreas Pircher, Dominik Wolf, Sieghart Sopper, Ronald Gust, Stefan Salcher","doi":"10.1021/acs.jmedchem.4c01865","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01865","url":null,"abstract":"The present structure–activity relationship study investigates the development of novel chemosensitizers targeting therapy-resistant cancer stem cells (CSCs). We used 4′-((2-propyl-1H-benzo[d]imidazole-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid, derived from the angiotensin II type 1 receptor blocker telmisartan, as a lead structure, demonstrating that the biphenyl moiety is essential for chemosensitizing activity. Introducing a methyl carboxylate or carboxamide instead of the COOH-group significantly enhanced this effect, leading to the development of highly potent compounds. These novel, noncytotoxic chemosensitizers effectively target CSCs and overcome drug resistance by interfering with CSC persistence mechanisms─hyperactivated STAT5 signaling and increased drug transporter activity─with demonstrated efficacy in leukemia, ovarian, and prostate cancers. The carboxamide of telmisartan (telmi-amide, 7c) significantly reduced tumor growth in an imatinib-resistant leukemia xenograft model, both as monotherapy and combined with imatinib, showing promising oral bioavailability and tolerability. In summary, telmisartan derivatives act as effective chemosensitizers and offer an innovative strategy for targeting CSCs in various malignant diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"204 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849176","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

Identification of an Isoxazole Derivative as an Antitubercular Compound for Targeting the FadD Enzymes of Mycobacterium tuberculosis

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-18 DOI: 10.1021/acs.jmedchem.4c01844

Nidhi Rani, Raju S. Rajmani, Avadhesha Surolia

{"title":"Identification of an Isoxazole Derivative as an Antitubercular Compound for Targeting the FadD Enzymes of Mycobacterium tuberculosis","authors":"Nidhi Rani, Raju S. Rajmani, Avadhesha Surolia","doi":"10.1021/acs.jmedchem.4c01844","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01844","url":null,"abstract":"FadD32, a fatty acyl-AMP ligase, plays an indispensable role in mycobacterial mycolic acid synthesis and is a validated target for tuberculosis (TB) drug development. The crystal structure of Mycobacterium tuberculosis (Mtb)FadD32 has laid the foundation of structure-based drug discovery against this crucial enzyme. Here, we screened the “isoxazole” scaffold containing molecules against MtbFadD32 and identified a compound 2,4-dibromo-6-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol (M1) with specific inhibitory activity against Mtb. Kinetics experiments showed that M1 inhibits MtbFadD32 and MtbFadD28 activity. The transcriptomics response of Mtb disclosed M1-mediated regulation of mycobacterial decisive genes involved in cell wall synthesis, consequently creating unfavorable conditions for Mtb survival. Further, M1 curtails the Mtb survival in infected macrophages and reduces Mtb burden and tubercular granulomas in a chronic infection model of BALB/c mice. Our findings provide an effective chemical scaffold to inhibit MtbFadD32 with the potential to inhibit multiple MtbFadD family of enzymes for further development as a promising candidate for treating TB.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849174","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

Hypoxia Activated Nitric Oxide Donor Compounds for the Prevention and Treatment of Myocardial Hypoxia-Induced Injury

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-18 DOI: 10.1021/acs.jmedchem.4c02132

Wanxiang Yang, Wen Zhou, Shaohua Gou

引用次数: 0

Impact of Linker Composition on VHL PROTAC Cell Permeability

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-18 DOI: 10.1021/acs.jmedchem.4c02492

Yordanos Esubalew Abeje, Lianne H. E. Wieske, Vasanthanathan Poongavanam, Stefanie Maassen, Yoseph Atilaw, Philipp Cromm, Lutz Lehmann, Mate Erdelyi, Daniel Meibom, Jan Kihlberg

引用次数: 0

Pivotal Role of the Intracellular Microenvironment in the High Photodynamic Activity of Cationic Phthalocyanines

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-17 DOI: 10.1021/acs.jmedchem.4c02451

Dmitry A. Bunin, Roman A. Akasov, Alexander G. Martynov, Maria P. Stepanova, Svetlana V. Monich, Aslan Yu. Tsivadze, Yulia G. Gorbunova

{"title":"Pivotal Role of the Intracellular Microenvironment in the High Photodynamic Activity of Cationic Phthalocyanines","authors":"Dmitry A. Bunin, Roman A. Akasov, Alexander G. Martynov, Maria P. Stepanova, Svetlana V. Monich, Aslan Yu. Tsivadze, Yulia G. Gorbunova","doi":"10.1021/acs.jmedchem.4c02451","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02451","url":null,"abstract":"To investigate the influence of phthalocyanine aggregation on their photodynamic activity, a series of six cationic water-soluble zinc(II) phthalocyanines bearing from four to sixteen 4-((diethylmethylammonium)methyl)phenoxy substituents was synthesized. Depending on their structure, the phthalocyanines have different aggregation behaviors in phosphate buffer solutions ranging from fully assembled to monomeric states. Remarkably, independent of aggregation in buffer, very high photodynamic efficiencies against the tumor cell lines MCF-7 and MDA-MB-231 in the nanomolar range were found for all investigated phthalocyanine, and the IC50(light) varied from 27 to 358 nM (3.5 J/cm2, 660 nm) with IC50(dark)/IC50(light) ratios up to ∼3700. This is due to the intracellular disassembly of aggregated phthalocyanines with the formation of monomeric photoactive forms, as demonstrated by fluorescence microscopy. Indeed, the interaction of aggregated phthalocyanines with serum proteins in a buffer resulted in the disassembly of nonluminescent aggregate species with the release of photoactive monomers bound to protein macromolecules.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832882","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

Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions 利用胺-酸偶联反应在系统水平上调节 BRD4 PROTAC 的效力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-17 DOI: 10.1021/acs.jmedchem.4c02047

Andrew McGrath, Haiyan Huang, Jean-Francois Brazeau, Zirong Zhang, Christopher O. Audu, Nadeem A. Vellore, Lu Zhu, Zhicai Shi, Jennifer D. Venable, Christine F. Gelin, Tim Cernak

{"title":"Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions","authors":"Andrew McGrath, Haiyan Huang, Jean-Francois Brazeau, Zirong Zhang, Christopher O. Audu, Nadeem A. Vellore, Lu Zhu, Zhicai Shi, Jennifer D. Venable, Christine F. Gelin, Tim Cernak","doi":"10.1021/acs.jmedchem.4c02047","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02047","url":null,"abstract":"Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds. While straightforward to synthesize, amides may impart suboptimal drug properties to the overall molecule. From a systems level perspective, we envisioned that the potency of PROTACs could be modulated through selection of reaction conditions─wherein different catalysts produce distinct linkers from the same two building blocks. We present a suite of BRD4 PROTAC degraders prepared via four new amine–acid coupling reactions alongside the classic amide coupling. Our findings reveal that variations in reaction conditions affect the physicochemical properties of PROTACs, resulting in a spectrum of properties. Notably, several new PROTACs demonstrated enhanced BRD4 degradation efficacy compared to those employing amide linkers, emphasizing the potential of systems chemistry as a therapeutic optimization strategy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"122 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833043","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 N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-12-17 DOI: 10.1021/acs.jmedchem.4c01786

Guangwei Cui, Yuhang Fan, Yue Yang, Yiwen Ma, Haiyang Deng, Pan Wang, Yuxin Zhu, Jian Li, Jinlian Wei, Yongqiang Zhang

{"title":"Discovery of N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma","authors":"Guangwei Cui, Yuhang Fan, Yue Yang, Yiwen Ma, Haiyang Deng, Pan Wang, Yuxin Zhu, Jian Li, Jinlian Wei, Yongqiang Zhang","doi":"10.1021/acs.jmedchem.4c01786","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01786","url":null,"abstract":"The search for new and effective chemotherapeutic agents for the treatment of glioblastoma (GBM) represents an unmet need in drug discovery. Herein, a class of novel N-trifluoromethylated noscapines has been disclosed. Among them, 9′-bromo-N-trifluoromethyl noscapine 15c displayed superior in vitro anti-GBM potency. Unexpectedly, in contrast with the general N-trifluoromethyl amines, these compounds exhibited good hydrolytic stability and further investigation of this distinct stability revealed a novel strategy for the structure modification of tetrahydroisoquinoline alkaloids, where N-methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, 15c showed excellent BBB permeability and good in vivo anti-GBM activity and could efficiently suppress the migration of GBM cells, while no apparent toxicity was observed, thus representing an attractive lead for further drug discovery. Further mechanistic studies revealed that 15c exhibited an ability to induce G2/M-phase arrest in GBM cells associated with the disruption of tubulin polymerization, which is consistent with the mechanism of action of noscapine.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832877","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