ChemMedChem最新文献_第6页

Novel Folate-Phenylfuran P-gp Inhibitor Conjugates for Overcoming Multidrug Resistance in MCF-7/ADR Cell. 新型叶酸-苯呋喃P-gp抑制剂偶联物克服MCF-7/ADR细胞多药耐药

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-14 DOI: 10.1002/cmdc.202500216

Qin Wang, Ning Yang, Hui Yan, Yunzhu Zhu, Qingyue Zhang, Rongqing Zhu, Yi Yang, Liang Yu, Yanyan Liu, Jiabin Li, Yasheng Li

{"title":"Novel Folate-Phenylfuran P-gp Inhibitor Conjugates for Overcoming Multidrug Resistance in MCF-7/ADR Cell.","authors":"Qin Wang, Ning Yang, Hui Yan, Yunzhu Zhu, Qingyue Zhang, Rongqing Zhu, Yi Yang, Liang Yu, Yanyan Liu, Jiabin Li, Yasheng Li","doi":"10.1002/cmdc.202500216","DOIUrl":"https://doi.org/10.1002/cmdc.202500216","url":null,"abstract":"P-glycoprotein (P-gp) functions as a critical membrane transporter that drives tumor resistance by mediating drug efflux, ultimately contributing to multidrug resistance (MDR). Recently potent inhibitors have shown significant potential in countering chemotherapeutic resistance, particularly in breast cancer. However, P-gp's presence in essential organs complicates clinical applications, underscoring the importance of developing tumor-specific targeting strategies. Given the high-level expression of folate receptors (FR) on the surface of breast cancer cells, this study conjugated a previously developed P-gp inhibitor with folic acid, with the goal of harnessing FR-mediated targeting for enhanced tumor cell specificity. In vitro evaluations reveal that the resultant conjugate maintains substantial resistance reversal efficacy against the MCF-7/ADR breast cancer-resistant cell line, comparable to the standalone inhibitor. The conjugate emerges as a highly potent and safe P-gp inhibitor in xenograft mouse, likely attributable to its enhanced tumor-targeting specificity, exhibiting superior in vivo efficacy when administered in combination with doxorubicin, relative to the original P-gp inhibitor.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500216"},"PeriodicalIF":3.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Design, Synthesis, and Evaluation of Boron Dipyrromethene-Based Fluorescent Probes Targeting BRAF for Melanoma Diagnosis. 基于BRAF的二吡咯烷硼荧光探针在黑色素瘤诊断中的设计、合成和评价

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-10 DOI: 10.1002/cmdc.202500095

Mengqian Wang, Weili Zhao, Xiaochun Dong

{"title":"Design, Synthesis, and Evaluation of Boron Dipyrromethene-Based Fluorescent Probes Targeting BRAF for Melanoma Diagnosis.","authors":"Mengqian Wang, Weili Zhao, Xiaochun Dong","doi":"10.1002/cmdc.202500095","DOIUrl":"https://doi.org/10.1002/cmdc.202500095","url":null,"abstract":"Fluorescent dyes are widely applied in clinical diagnosis, detection, and treatment of diseases. Several image probes such as ICG, MB, and 5-ALA have been approved by FDA. However, the limited tumor-targeting capability of these dyes hinders their effectiveness in oncological imaging. Currently, various ligand-based targeting probes have been developed to minimize nonspecific background emission. BRAF, especially BRAF V600E, is a common cancer gene and undergoes frequent mutation in melanoma. Small molecular BRAF kinase inhibitors have been approved for the treatment of melanoma patients carrying the BRAF V600E mutation, including Vemurafenib, Dabrafenib and so on. Boron dipyrromethene (BODIPY) as an important fluorescent class has been investigated extensively. Vemurafenib-BODIPY has been reported to visualize BRAF V600E mutated cancer cells. Herein, the designed BODIPY-based Vemurafenib derivatives targeting BRAF for cancer cell imaging are reported. The fluorescent probes are characterized and evaluated of photophysical properties, targeted binding and live cell imaging. Compound 1a exhibited promising fluorescence imaging ability. To improve fluorescence quantum yield, structural optimization is performed by incorporating meso N,N'-dialkyl-substituted amides to BODIPY core. Compound 1d shows excellent fluorescence properties and nice binding affinity. It allows visualization of BRAF V600E mutated cancer cells at low concentrations.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500095"},"PeriodicalIF":3.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Design, Synthesis and Biological Evaluation of N6-Substituted-C2-Alkynyl-4'-Thionucleoside and 4'-Trucatedthionucleoside Derivatives as Novel A₃ Adenosine Receptor Ligands. 新型A3腺苷受体配体n6 -取代- c2 -炔基-4′-硫代核苷及4′-结构硫代核苷衍生物的设计、合成及生物学评价

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-10 DOI: 10.1002/cmdc.202500135

Vikas R Aswar, Dnyandev B Jarhad, Jiyoon Song, Jinha Yu, Lak Shin Jeong

{"title":"Design, Synthesis and Biological Evaluation of N6-Substituted-C2-Alkynyl-4'-Thionucleoside and 4'-Trucatedthionucleoside Derivatives as Novel A3 Adenosine Receptor Ligands.","authors":"Vikas R Aswar, Dnyandev B Jarhad, Jiyoon Song, Jinha Yu, Lak Shin Jeong","doi":"10.1002/cmdc.202500135","DOIUrl":"https://doi.org/10.1002/cmdc.202500135","url":null,"abstract":"Adenosine receptors (ARs) play crucial roles in various physiological processes, making them significant targets for therapeutic intervention. This study focuses on the design, synthesis, and evaluation of N6-substituted-C2-alkynyl-4'-thioadenosine and truncated 4'-thioadenosine derivatives as selective ligands for the human A3 adenosine receptor (hA3 AR). Binding affinity assays demonstrated that modifications at the C2-alkyne and N6-amine positions significantly influenced receptor selectivity and potency. Compound 3b showed high affinity for hA3 AR (Ki = 1.8 nM) with excellent subtype selectivity and acted as an agonist. In contrast, truncated derivative 6b was an antagonist, while 6s, which shares the same sugar structure as 6b, functioned as a partial agonist, highlighting the roles of sugar and base moieties in ligand function. Molecular docking studies provided further insight into distinct binding modes, demonstrating the impact of minor structural variations on ligand-receptor binding dynamics. These findings contribute to the development of potent and selective A3 AR modulators by emphasizing the importance of fine structural adjustments in ligand design.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500135"},"PeriodicalIF":3.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Employing a Highly Potent Fluorescence Probe to Discover a PARP-1/2 Binder and the Complex Structures Analysis. 利用高效荧光探针发现PARP-1/2结合物及其复杂结构分析。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-09 DOI: 10.1002/cmdc.202500168

Xiaoyu Wang, Chengyan Wang, Jinruo Li, Jie Zhou, Bailing Xu

{"title":"Employing a Highly Potent Fluorescence Probe to Discover a PARP-1/2 Binder and the Complex Structures Analysis.","authors":"Xiaoyu Wang, Chengyan Wang, Jinruo Li, Jie Zhou, Bailing Xu","doi":"10.1002/cmdc.202500168","DOIUrl":"https://doi.org/10.1002/cmdc.202500168","url":null,"abstract":"Poly (ADP-ribose) polymerases-1/2(PARP-1/2) has been identified as important anti-tumor drug targets, and the development of PARP-1/2 inhibitors featuring novel structures is still a promising strategy for cancer treatments. In this work, a highly potent PARP-1/2 probe with a quinazolinone scaffold was designed and synthesized, showing dissociation constants (Kd) of 2.07 nM and 1.6 nM towards catPARP-1 and catPARP-2SE. By employing this probe to screen an in-house compound library, compound A bearing a pyrazolo[1,5-a]pyrimidine-3-carboxamide scaffold was disclosed as a structurally novel PARP-1/2 binder, which had dissociation constants of 5.6 μM and 7.9 μM for catPARP-1 and catPARP-2SE in the Isothermal Titration Calorimetry (ITC) assay. Moreover, the crystal structures of compound A in complex with PARP-1 and PARP-2 catalytic domains were solved to reveal the binding modes of this compound, and these two complex structures were analyzed with IGMH method at GFN2-xTB and B3LYP levels. Interestingly, this compound presented significant differences in binding modes within PARP-1 and PARP-2. These results could provide a structural basis for the discovery of novel PARP-1 or PARP-2 selective inhibitors by taking compound A as a template structure.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500168"},"PeriodicalIF":3.6,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Nitidine and Paclitaxel co-loaded lipid-chitosan hybrid nanoparticles overcome ABCB1-mediated multidrug resistance in ovarian cancer. 尼替丁和紫杉醇共载脂质-壳聚糖混合纳米颗粒克服abcb1介导的卵巢癌多药耐药。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500065

Rabia Yilmaz Ozturk, Elif Durasi, Hilal Çalık, Selcen Ari Yuka, Rabia Cakir Koc

{"title":"Nitidine and Paclitaxel co-loaded lipid-chitosan hybrid nanoparticles overcome ABCB1-mediated multidrug resistance in ovarian cancer.","authors":"Rabia Yilmaz Ozturk, Elif Durasi, Hilal Çalık, Selcen Ari Yuka, Rabia Cakir Koc","doi":"10.1002/cmdc.202500065","DOIUrl":"https://doi.org/10.1002/cmdc.202500065","url":null,"abstract":"Multiple drug resistance, which leads to tumor recurrence and contributes to high mortality rates in ovarian cancer, is a significant issue that must be overcome for successful treatment. Within this study, we explored the efficacy of lipid-chitosan hybrid nanoparticles with NTD as an ABCB1 inhibitor and PTX as a chemotherapeutic agent in ABCB1 overexpressed ovarian cancer cells. Sensitive ovarian cancer cells acquired resistance by continuous paclitaxel treatment and confirmed by the resistance index and ABCB1 expression by qRT-PCR. PTX-NTD-loaded lipid-chitosan hybrid nanoparticles (N-PTX-LPHNPs) were synthesized via ionic gelation and characterized by the DLS method, in vitro release, encapsulation and loading efficiency, FT-IR and SEM. XTT, Rho-123 accumulation assay, and DCFH-DA staining were conducted to examine the drug resistance inhibition and anti-cancer activity of NTD and N-PTX-LPHNPs. Bioinformatics analyzes were performed to evaluate the ADME/T properties of NTD and the interaction between the PTX-NTD combination and ABCB1. NTD showed high binding affinity to ABCB1 and had cytotoxicity against ovarian cancer cells. Moreover, the PTX-NTD drug combination loaded nanoparticles increased PTX accumulation and intracellular ROS levels, enhanced anti-cancer activity, and overcame resistance to ovarian cancer. Our results highlight the NTD-PTX-loaded lipid-chitosan hybrid nanoparticles as a potential therapeutic for ABCB1 overexpressed ovarian cancer.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500065"},"PeriodicalIF":3.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Is Mycobacterial InhA a Suitable Target for Rational Drug Design? InhA分枝杆菌是合理设计药物的合适靶点吗？

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500079

Julien Rizet, Laurent Maveyraud, David Rengel, Valérie Guillet, Gabriel Publicola, Frédéric Rodriguez, Christian Lherbet, Lionel Mourey

{"title":"Is Mycobacterial InhA a Suitable Target for Rational Drug Design?","authors":"Julien Rizet, Laurent Maveyraud, David Rengel, Valérie Guillet, Gabriel Publicola, Frédéric Rodriguez, Christian Lherbet, Lionel Mourey","doi":"10.1002/cmdc.202500079","DOIUrl":"10.1002/cmdc.202500079","url":null,"abstract":"InhA, an NAD-dependent enoyl-acyl carrier protein reductase, is involved in the biosynthesis of mycolic acids, specific lipids to mycobacteria. InhA is the target of isoniazid, a first-line antituberculosis drug used since the 1950s. Isoniazid is a prodrug that needs to be activated by the catalase-peroxidase KatG. Due to resistance problems, a substantial amount of work has been carried out to identify or design direct inhibitors of InhA, demonstrating that this enzyme is still considered a relevant target for the discovery of new antituberculosis drugs. Much of this work included the resolution of crystallographic structures. Indeed, over a hundred structures have been deposited in the Protein Data Bank for different forms of the enzyme (apo, holo, and complexes), demonstrating a real crystalline polymorphism. Taken together, these structures constitute a valuable dataset. However, the complete decoding of the enzyme's properties and its inhibition literally comes up against its molecular plasticity at the level of a motif essential to the definition of the active site: the substrate-binding loop. In this article, a detailed analysis of this structural dataset is proposed, describing in particular the different families of inhibitors and attempting to establish structural links of causality.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500079"},"PeriodicalIF":3.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Deferasirox Derivatives as Inhibitors of Kallikrein-Related Peptidases Associated to Neurodegenerative Diseases. 去铁素衍生物作为与神经退行性疾病相关的钾化钾相关肽酶抑制剂

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500187

Rilès Boumali, Elodie David, Nancy Chaaya, Morane Lucas, Sabrina Aït Amiri, Valérie Lefort, Anthony Nina-Diogo, Michèle Salmain, Isabelle Petropoulos, Vincent Corcé, Chahrazade El Amri, Candice Botuha

{"title":"Deferasirox Derivatives as Inhibitors of Kallikrein-Related Peptidases Associated to Neurodegenerative Diseases.","authors":"Rilès Boumali, Elodie David, Nancy Chaaya, Morane Lucas, Sabrina Aït Amiri, Valérie Lefort, Anthony Nina-Diogo, Michèle Salmain, Isabelle Petropoulos, Vincent Corcé, Chahrazade El Amri, Candice Botuha","doi":"10.1002/cmdc.202500187","DOIUrl":"10.1002/cmdc.202500187","url":null,"abstract":"Kallikrein-related peptidases are a family of serine proteases whose loss of activity regulation has been particularly linked to neurodegenerative diseases. Moreover, iron overload is also a key process in some of these leading pathological conditions, particularly Alzheimer's disease. It is identified for the first time Deferasirox, a well-known FDA-approved iron chelator (DFX) as an initial hit for kallikrein's (KLK) inhibition and proposed here the design and synthesis of a small library of molecules using DFX as chemical scaffold. Resulting subseries of compounds are evaluated against lead central nervous system KLK's, namely, KLK1, KLK6, and KLK8 using targeted pharmacomodulations on DFX. Beyond DFX, several reversible micromolar inhibitors of these KLKs have been identified as hits and are shown to be devoid of any noticeable cytotoxicity toward neural cell lines commonly used in the field of neurodegenerative diseases. Their ability to chelate iron is also assessed in comparison to DFX and preformed iron-compound complexes displayed slightly improved inhibition potency for some derivatives with a KLK-dependent manner. Hence, several DFX derivatives are identified as promising starting points for the development of dual therapeutic agents in the context of neurodegenerative diseases where both deregulated KLK's proteolysis and iron dysregulation are involved.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500187"},"PeriodicalIF":3.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Novel Aminopyrimidines as Selective EP2 Receptor Antagonists. 新型氨基嘧啶选择性EP2受体拮抗剂的发现。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500119

Isabelle Lyothier, Stefan Diethelm, Julien Pothier, Thierry Sifferlen, Davide Pozzi, Sylvia Richard-Bildstein, Hervé Siendt, Heinz Fretz, Christoph Boss, Lorenza Wyder, Sébastien Jeay, Ruben de Kanter, Carmela Gnerre, François Lehembre, Dominique S Meyer, Olivier Corminboeuf

引用次数: 0

Improved C5-Amide Bioisosteres for Human Neuraminidase 1 Inhibitors Based on 2-Deoxy-2,3-Didehydro-N-Acetyl Neuraminic Acid. 基于2-脱氧-2,3-二脱氢- n -乙酰神经氨酸（DANA）的人神经氨酸酶1抑制剂c5 -酰胺生物异构体的改进

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500099

Mostafa Radwan, Elisa G Carvajal, Christopher W Cairo

{"title":"Improved C5-Amide Bioisosteres for Human Neuraminidase 1 Inhibitors Based on 2-Deoxy-2,3-Didehydro-N-Acetyl Neuraminic Acid.","authors":"Mostafa Radwan, Elisa G Carvajal, Christopher W Cairo","doi":"10.1002/cmdc.202500099","DOIUrl":"10.1002/cmdc.202500099","url":null,"abstract":"Neuraminidase enzymes (NEU) play a crucial role in many physiological and pathological conditions. Humans have four isoenzymes of NEU, and their specific roles continue to be investigated. Isoenzyme-selective inhibitors are needed as research tools and may lead to future therapeutics. A series of new candidate inhibitors are tested by replacing the C5-amide of 2-deoxy-2,3-dididehydro-N-acetyl neuraminic acid with amide bioisosteres. Design of candidate inhibitors is accomplished using substituents that are components of previously identified NEU inhibitors combined with alternative amide bioisosteres. Compounds are tested for inhibition of the four human NEU, and inhibitory activities are compared to reference amide compounds. 1,4-Disubstituted-1,2,3-triazole is the best bioisostere observed for inhibitors of NEU1. Inhibitor 542 shows high potency for NEU1 (Ki = 0.4 ± 0.1 μM) and give significant improvement in selectivity compared to the reference amide compound 502. Additionally, compound 542 has improved lipophilic characteristics, which could provide improved pharmacokinetic properties. Screening of these inhibitors also identify a selective NEU2 inhibitor 543 (Ki = 2.6 ± 0.6 μM), illustrating that amide bioisostere replacement can identify improved inhibitors for multiple NEU isoenzymes.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500099"},"PeriodicalIF":3.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

First Phosphonic-Type Inhibitors and Activity-Based Probes Specific to the O'nyong-nyong Virus Capsid Protease. 第一个针对O'nyong-nyong病毒衣壳蛋白酶的膦型抑制剂和基于活性的探针。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-07 DOI: 10.1002/cmdc.202500049

Karolina Torzyk-Jurowska, Agnieszka Łupicka-Słowik, Renata Grzywa, Yuliya Chykunova, Krzysztof Pyrć, Marcin Sieńczyk

引用次数: 0