Bioorganic & Medicinal Chemistry Letters最新文献_第5页

Design, synthesis of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivatives as potential anticancer agents 设计、合成2,3,4,9-四氢- 1h -吡哆[3,4-b]吲哚衍生物作为潜在的抗癌剂

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2026-01-06 DOI: 10.1016/j.bmcl.2026.130535

Yaxi Xu , Yupei Sun , Zongwei Yu , Xiangyang Zhang , Zhiming Liu , Jianzeng Xin , Sheng Liu , Feng Zhao

{"title":"Design, synthesis of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivatives as potential anticancer agents","authors":"Yaxi Xu , Yupei Sun , Zongwei Yu , Xiangyang Zhang , Zhiming Liu , Jianzeng Xin , Sheng Liu , Feng Zhao","doi":"10.1016/j.bmcl.2026.130535","DOIUrl":"10.1016/j.bmcl.2026.130535","url":null,"abstract":"<div><div>The tetrahydro-β-carboline (THβC) scaffold is a promising chemotype in anticancer drug discovery whose development is hindered by poor aqueous solubility and underexplored functionalization at the N-2 position. To overcome these limitations, we designed a series of novel THβC derivatives via molecular hybridization at the N-2 site using natural unsaturated carboxylic acids, aiming to improve solubility and biological activity. Among the synthesized compounds, derivative <strong>9</strong> exhibited potent and selective anti-proliferative activity against MCF-7 breast cancer cells. Based on this promising activity, we first investigated its effect on key oncogenic pathways. Western blot analysis revealed that compound <strong>9</strong> significantly downregulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) without affecting the NF-κB p65 subunit, suggesting a selective mechanism of action. Subsequent molecular docking studies provided a structural rationale for this selectivity, showing favorable binding modes of <strong>9</strong> within the ERK1/2 kinase domains. Collectively, this work establishes N-2 functionalization as a viable strategy for developing THβC-based anticancer agents with optimized pharmacological profiles.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130535"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921991","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 multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases 发现多靶点单一药物作为神经退行性疾病潜在治疗的新途径

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2026-01-07 DOI: 10.1016/j.bmcl.2026.130536

Jeetal Vyas , Anuj S. Jamenis , Krishna Kaku , Yesha Shah , Kristin M. Miner , Tarun N. Bhatia , Roxanne E. Kim , Ruoli Bai , Ernest Hamel , Rehana K. Leak , Aleem Gangjee

{"title":"Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases","authors":"Jeetal Vyas , Anuj S. Jamenis , Krishna Kaku , Yesha Shah , Kristin M. Miner , Tarun N. Bhatia , Roxanne E. Kim , Ruoli Bai , Ernest Hamel , Rehana K. Leak , Aleem Gangjee","doi":"10.1016/j.bmcl.2026.130536","DOIUrl":"10.1016/j.bmcl.2026.130536","url":null,"abstract":"<div><div>There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds <strong>1</strong> and <strong>2</strong>) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS <em>in vivo</em>. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130536"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922060","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

Identification of a novel Songorine derivative as a potent NLRP3 inflammasome inhibitor 一种新型松果碱衍生物作为一种有效的NLRP3炎性体抑制剂的鉴定

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-19 DOI: 10.1016/j.bmcl.2025.130511

Runqin Liu , Qiang Zhang , Miao Xian , Qifeng Chen

{"title":"Identification of a novel Songorine derivative as a potent NLRP3 inflammasome inhibitor","authors":"Runqin Liu , Qiang Zhang , Miao Xian , Qifeng Chen","doi":"10.1016/j.bmcl.2025.130511","DOIUrl":"10.1016/j.bmcl.2025.130511","url":null,"abstract":"<div><div>As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 activation contributes to various chronic inflammatory diseases, including atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, underscoring its therapeutic relevance. In this study, we designed and synthesized compound <strong>8a</strong>, a structurally optimized derivative of the diterpenoid alkaloid songorine. In lipopolysaccharide (LPS)- and nigericin-stimulated macrophage models, <strong>8a</strong> markedly reduced lactate dehydrogenase (LDH) release (IC₅₀ = 2.69 μM in THP-1 cells and 1.75 μM in J774A.1 cells) and effectively inhibited gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) secretion, demonstrating potent suppression of pyroptosis. Hydrogenation of the C16–C17 double bond afforded compound <strong>8b</strong>, which lost inhibitory activity, indicating that the α,β-unsaturated carbonyl moiety is essential for function, likely via covalent modification of cysteine residues on NLRP3. This mechanism was further substantiated by Drug Affinity Responsive Target Stability (DARTS) assays and mass spectrometry, confirming direct binding between <strong>8a</strong> and NLRP3. We also conducted structure–activity relationship studies by modifying the C1 position and found that such modifications did not significantly impact the compound's activity. Collectively, these findings identify <strong>8a</strong> as a novel songorine-derived covalent NLRP3 inhibitor and provide the first elucidation of its structure–activity relationship and molecular mechanism, offering valuable insights for the rational design of safe and effective anti-inflammatory agents targeting NLRP3.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130511"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801941","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 antiviral activity evaluation of the bis-ester prodrug of N4-hydroxycytidine phosphate 磷酸n4 -羟基胞苷双酯前药的设计、合成及抗病毒活性评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-25 DOI: 10.1016/j.bmcl.2025.130525

Hao Sun , Xu Yan , Chunhuan Mo , Jia Chen , Yan Liu , Yaohui Liu , Xia Han , Jianqin Gao , Lehua Yin , Jinghua Xu , Yuan Chen , Xinhua He

{"title":"Design, synthesis, and antiviral activity evaluation of the bis-ester prodrug of N4-hydroxycytidine phosphate","authors":"Hao Sun , Xu Yan , Chunhuan Mo , Jia Chen , Yan Liu , Yaohui Liu , Xia Han , Jianqin Gao , Lehua Yin , Jinghua Xu , Yuan Chen , Xinhua He","doi":"10.1016/j.bmcl.2025.130525","DOIUrl":"10.1016/j.bmcl.2025.130525","url":null,"abstract":"<div><div>Monophosphorylation is a key rate-limiting step for the efficacy of broad-spectrum nucleoside antiviral drugs, and designing phosphate prodrugs is an effective method to enhance antiviral efficacy. <em>N4</em>-hydroxycytidine (NHC) has a broad-spectrum antiviral effect. Based on the mechanism of action and metabolic inactivation characteristics of NHC, we designed a series of dual ester prodrugs targeting the N4-hydroxyl group and the 5′-phosphate of the ribose ring. Twenty-nine compounds were designed and synthesized. The cytotoxicity assay results showed low cytotoxicity (no significant toxicity at 160 μM). Using the Vesicular Stomatitis Virus expressing Green Fluorescent Protein (VSV-GFP) virus screen, it was found that all of them have antiviral activity. Compounds 2328 and 2322 showed better antiviral activity than molnupiravir. The EC<sub>50</sub>s of 2328 against VSV, HMPV-A2, and RSV-A2 viruses were 2.19 μM, 35.6 μM, and 53.5 μM, respectively, and the EC<sub>50</sub>s of 2322 against VSV, HMPV-A2, and RSV-A2 were 6.23 μM, 52.8 μM, and 28.2 μM, respectively. Structure-activity relationships indicate that the antiviral activity of compounds at the cellular level is closely linked to the structure of the prodrug's phosphate ester, whereas the ester group on the <em>N4</em>-hydroxyl is more tolerant of diverse functional groups.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130525"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846166","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

Inhibitory effects of diterpenoids from Celastrus rosthornianus Lose. on lipid accumulation 红桃芹中二萜类化合物的抑制作用。关于脂质积累

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2026-01-08 DOI: 10.1016/j.bmcl.2026.130538

Yangyang Chen , Ruiqiong Li , Yuanping Chen , Chi Li , Mengting Pan , Peipei Chen , Yanling Jiang , Jiani Chen , Zehao Huang , Yaqian Feng , Yali Wang , Hua Li , Shaohua Xu

引用次数: 0

AI-guided design of cyclic peptide binders targeting TREM2 using CycleRFdiffusion and experimental validation 基于CycleRFdiffusion的针对TREM2的环肽结合物ai引导设计及实验验证

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-21 DOI: 10.1016/j.bmcl.2025.130512

Sungwoo Cho , Renjie Zhu , Katarzyna Kuncewicz , Hongliang Duan , Moustafa Gabr

{"title":"AI-guided design of cyclic peptide binders targeting TREM2 using CycleRFdiffusion and experimental validation","authors":"Sungwoo Cho , Renjie Zhu , Katarzyna Kuncewicz , Hongliang Duan , Moustafa Gabr","doi":"10.1016/j.bmcl.2025.130512","DOIUrl":"10.1016/j.bmcl.2025.130512","url":null,"abstract":"<div><div>Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimer's disease. Despite advances in antibody-based therapeutics, small molecules and peptides capable of modulating TREM2 remain limited. Here, we present a cyclic peptide design pipeline that integrates CycleRFdiffusion, ProteinMPNN for sequence design, and HighFold for structural prediction and screening. Using the TREM2 structure as input, we generated and screened 1500 peptide–target complexes, prioritizing four candidates that met structural and energetic criteria. Subsequent biophysical evaluation identified <strong>TP4</strong> as a weak but reproducible TREM2 binder, demonstrating consistent binding in spectral shift, microscale thermophoresis, and surface plasmon resonance. Pharmacokinetic profiling indicated that <strong>TP4</strong> possesses favorable plasma stability and moderate metabolic stability, supporting its potential for further optimization. This study establishes a generalizable framework for AI-driven cyclic peptide discovery and provides the first proof-of-concept demonstration of TREM2-targeted cyclic peptide binders.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130512"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801940","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

Correlation between tight binding of inhibitors and their target selectivity toward the non-native state in the DYRK family of kinases 在DYRK激酶家族中，抑制剂的紧密结合与它们对非天然状态的靶向选择性之间的关系。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-27 DOI: 10.1016/j.bmcl.2025.130527

Natsumi Yamada , Sora Suzuki , Nanae Fukahori , Yoshiyuki Yamaoka , Yuta Komiyama , Ninako Kimura , Koji Umezawa , Isao Kii

{"title":"Correlation between tight binding of inhibitors and their target selectivity toward the non-native state in the DYRK family of kinases","authors":"Natsumi Yamada , Sora Suzuki , Nanae Fukahori , Yoshiyuki Yamaoka , Yuta Komiyama , Ninako Kimura , Koji Umezawa , Isao Kii","doi":"10.1016/j.bmcl.2025.130527","DOIUrl":"10.1016/j.bmcl.2025.130527","url":null,"abstract":"<div><div>A folding intermediate of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in the non-native state autophosphorylates intramolecularly, whereas the folded conformation of DYRK1A in the native state no longer catalyzes this reaction. We identified FINDY, a small molecule that selectively inhibits the DYRK1A folding intermediate but not its fully folded conformation. These findings indicated the presence of a unique binding site that is exposed only in the folding intermediate. In the previous study, we developed a facile method for screening of inhibitors that target the folding intermediate in the non-native state using recombinant folded proteins in the native state. We found that FINDY and its derivatives target both DYRK1A and DYRK1B in their non-native states. In this study, we examined the potency of these inhibitors on DYRK2, another member of the DYRK family. FINDY inhibited DYRK2 in the non-native state slightly greater than that in the native state. Although RD0448, a FINDY derivative, selectively targets DYRK1A/1B in their non-native states, RD0448 exhibited no selectivity between the native and non-native states of DYRK2, indicating that the RD0448-binding site is hidden in the native state of DYRK1A/1B but is exposed in the native state of DYRK2. Furthermore, RD0448 bound tightly to DYRK1A/1B, whereas RD0448 showed weak affinity for DYRK2 and rapidly dissociated from the binding complex. These results suggest a correlation between the tight binding of the inhibitors and their target selectivity toward the non-native state in DYRK family kinases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130527"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145852768","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

Development of the fluorescence polarization-based competition assay for the E3 ligase GID4 基于荧光偏振的E3连接酶GID4竞争测定方法的建立。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-27 DOI: 10.1016/j.bmcl.2025.130528

Meiling Zhang , Shijia Xiao , Kexin Yan , Jiyue Sun , Chen Xi , Yuhong Qin , Cheng Dong , Dongxing Chen

{"title":"Development of the fluorescence polarization-based competition assay for the E3 ligase GID4","authors":"Meiling Zhang , Shijia Xiao , Kexin Yan , Jiyue Sun , Chen Xi , Yuhong Qin , Cheng Dong , Dongxing Chen","doi":"10.1016/j.bmcl.2025.130528","DOIUrl":"10.1016/j.bmcl.2025.130528","url":null,"abstract":"<div><div>The proteolysis-targeting chimera (PROTAC) technology utilizes heterobifunctional molecules to induce targeted protein degradation through the ubiquitin-proteasome system. Structurally, PROTAC molecules consist of a target protein ligand and an E3 ligase ligand covalently linked by a suitable linker arm, forming the target protein-PROTAC-E3 ligase stable ternary complex and bringing the target protein in proximity to the E3 ligase for ubiquitination and subsequent proteasomal degradation. However, only a few E3 ligases have been used to generate effective PROTACs with limited small molecule E3 ligase ligands. Therefore, there is an urgent need to discover novel E3 ligase ligands to expand the toolbox for PROTACs. Unlike traditional E3 ligases such as ‌CRBN‌ and ‌VHL‌, GID4 E3 ligase recognizes substrates bearing N-terminal proline or other small residues through the Pro/N-degron pathway, and has already been successfully leveraged in ‌PROTAC technology. Here, we reported the development of a fluorescent probe <strong>YG11</strong>, with a K<sub>d</sub> value of 8.1 ± 0.7 nM for GID4. With this probe, we established a robust fluorescence polarization (FP)-based competition assay for evaluation of GID4 ligands. The assay exhibited a high signal-to-noise ratio of over 20, 2.5 % DMSO tolerance, and a Z'-factor of 0.84, confirming its suitability and robustness for high-throughput screening. Thus, by enabling rapid identification of GID4 ligands, this FP competition assay promises to substantially advance PROTAC development initiatives.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130528"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145852801","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 4-aminobenzamide derivatives as small molecule CBX2 inhibitors 新型4-氨基苯甲酰胺衍生物小分子CBX2抑制剂的发现。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-30 DOI: 10.1016/j.bmcl.2025.130526

Yuichiro Kawamoto , Shohei Takase , Kumar Ashutosh , Hiroki Maruo , Yuki Maemoto , Kam Y.J. Zhang , Hisanaka Ito , Akihiro Ito

引用次数: 0

Second generation PSMA-targeted turn-on probe for imaging cargo release in prostate cancer cells 第二代psma靶向开启探针用于成像前列腺癌细胞中的货物释放。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-04-01 Epub Date: 2025-12-31 DOI: 10.1016/j.bmcl.2025.130530

Nooshin Mesbahi , Brenna C. McAllister , Hosog Yoon , Aaron T. Hendricksen , Melody D. Fulton , Leslie A. Caromile , Clifford E. Berkman

引用次数: 0