Pub Date : 2026-03-01Epub Date: 2025-12-18DOI: 10.1016/j.bmcl.2025.130510
Wenwen Nie , Baoli Ding , Xiaotong Chen , Li Jiang , Qiaojun He , Ji Cao , Cheng-Liang Zhu
Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.
{"title":"Multifaceted roles of HDAC7 in disease and the evolving chemical toolkit for its modulation","authors":"Wenwen Nie , Baoli Ding , Xiaotong Chen , Li Jiang , Qiaojun He , Ji Cao , Cheng-Liang Zhu","doi":"10.1016/j.bmcl.2025.130510","DOIUrl":"10.1016/j.bmcl.2025.130510","url":null,"abstract":"<div><div>Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130510"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797624","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}
Pub Date : 2026-03-01Epub Date: 2025-11-20DOI: 10.1016/j.bmcl.2025.130480
Jiyun Zhu , Sara Gutkin , Shiyu Chen , Shih-Po Su , Hai Phan , Doron Shabat , Matthew Bogyo
The cysteine cathepsins are a family of proteases that are widely expressed in diverse cell types. However, because their activity is highly upregulated at sites of inflammation, they are ideal targets for imaging a range of disease pathologies including cancer, atherosclerosis, fibrosis and others. While significant advances have been made in generation of activatable ‘smart’ probes for cathepsin activity, virtually all of these agents use fluorescent reporters which require a laser light source to induce a signal from the probe. We describe here the development and application of chemiluminescent probes for imaging cysteine cathepsin activity in cells and tissues. These probes provide rapid signal generation with low background in cells and tissues without the need for a light source. We demonstrate that a cathepsin probe containing an optimal peptide sequence can be used topically to detect activity in tumor tissues, demonstrating the potential value of this approach for real-time diagnosis of cancer as well as other conditions involving inflammation.
{"title":"Chemiluminescent probes for imaging cysteine cathepsin activity","authors":"Jiyun Zhu , Sara Gutkin , Shiyu Chen , Shih-Po Su , Hai Phan , Doron Shabat , Matthew Bogyo","doi":"10.1016/j.bmcl.2025.130480","DOIUrl":"10.1016/j.bmcl.2025.130480","url":null,"abstract":"<div><div>The cysteine cathepsins are a family of proteases that are widely expressed in diverse cell types. However, because their activity is highly upregulated at sites of inflammation, they are ideal targets for imaging a range of disease pathologies including cancer, atherosclerosis, fibrosis and others. While significant advances have been made in generation of activatable ‘smart’ probes for cathepsin activity, virtually all of these agents use fluorescent reporters which require a laser light source to induce a signal from the probe. We describe here the development and application of chemiluminescent probes for imaging cysteine cathepsin activity in cells and tissues. These probes provide rapid signal generation with low background in cells and tissues without the need for a light source. We demonstrate that a cathepsin probe containing an optimal peptide sequence can be used topically to detect activity in tumor tissues, demonstrating the potential value of this approach for real-time diagnosis of cancer as well as other conditions involving inflammation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130480"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581582","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}
Pub Date : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.bmcl.2025.130496
Jinyu Bai , Huaihuai Shi , Jitun Chen , Hui Tian , Jiaxin Liang , Bichun Chen , Jiazhong Li , Lijing Fang
Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.
{"title":"Bicyclic peptide-based CPPTACs for extracellular and cell membrane protein degradation","authors":"Jinyu Bai , Huaihuai Shi , Jitun Chen , Hui Tian , Jiaxin Liang , Bichun Chen , Jiazhong Li , Lijing Fang","doi":"10.1016/j.bmcl.2025.130496","DOIUrl":"10.1016/j.bmcl.2025.130496","url":null,"abstract":"<div><div>Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130496"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719941","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}
Pub Date : 2026-03-01Epub Date: 2025-12-10DOI: 10.1016/j.bmcl.2025.130500
Xiang Qiu , Lingling Dong , Hongzhen Shu , Guangxing Yu , Yuling Tong , Hengfan Ni , Shunjie Zhang
Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound 24 emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC50 value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound 24 efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC50 value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound 24 effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound 24 was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.
{"title":"Design, synthesis and biological evaluation of coumarin-based HDAC6 inhibitors for the treatment of ulcerative colitis","authors":"Xiang Qiu , Lingling Dong , Hongzhen Shu , Guangxing Yu , Yuling Tong , Hengfan Ni , Shunjie Zhang","doi":"10.1016/j.bmcl.2025.130500","DOIUrl":"10.1016/j.bmcl.2025.130500","url":null,"abstract":"<div><div>Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound <strong>24</strong> emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC<sub>50</sub> value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound <strong>24</strong> efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC<sub>50</sub> value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound <strong>24</strong> effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound <strong>24</strong> was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130500"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740259","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}
Pub Date : 2026-03-01Epub Date: 2025-12-12DOI: 10.1016/j.bmcl.2025.130506
Hafsa Ouaakki , Eduardo Bravo Jr , Justin Taylor , Yangbo Feng
STK17A (serine/threonine kinase 17a), also known as DRAK1 (death-associated protein kinase-related apoptosis-inducing protein kinase 1), is a member of the death-associated protein kinase (DAPK) family and acts as a positive regulator of apoptosis. STK17A is a dark kinase and is an understudied member in the DAPK family. Thus far, it has been found to serve a significant role in cell proliferation, apoptosis, tumor metastasis, and tumorigenesis. This review summarizes the structure of STK17A, its reported biological functions, and expression in cancer. Small molecule inhibitors for STK17A, including those specifically developed for STK17A and those designed for other kinases but also inhibit STK17A as an unintended target, are discussed. Finally, some outlooks for drug discovery regarding STK17A are described.
{"title":"Therapeutic potential of STK17A targeted therapies","authors":"Hafsa Ouaakki , Eduardo Bravo Jr , Justin Taylor , Yangbo Feng","doi":"10.1016/j.bmcl.2025.130506","DOIUrl":"10.1016/j.bmcl.2025.130506","url":null,"abstract":"<div><div>STK17A (serine/threonine kinase 17a), also known as DRAK1 (death-associated protein kinase-related apoptosis-inducing protein kinase 1), is a member of the death-associated protein kinase (DAPK) family and acts as a positive regulator of apoptosis. STK17A is a dark kinase and is an understudied member in the DAPK family. Thus far, it has been found to serve a significant role in cell proliferation, apoptosis, tumor metastasis, and tumorigenesis. This review summarizes the structure of STK17A, its reported biological functions, and expression in cancer. Small molecule inhibitors for STK17A, including those specifically developed for STK17A and those designed for other kinases but also inhibit STK17A as an unintended target, are discussed. Finally, some outlooks for drug discovery regarding STK17A are described.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130506"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754959","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}
Pub Date : 2026-03-01Epub Date: 2025-11-28DOI: 10.1016/j.bmcl.2025.130489
Xudong Pang , Dawei Cui , Ruifeng Liu , Binhua Lv , Cheng-Yun Wang
NASH represents an increasingly prevalent chronic liver disease, and TZDs are investigated as a potential therapeutic strategy. However, the inherent enolic structure of TZDs leads to enantiomeric instability and racemization, often requiring their use as racemic mixtures. We here report the development of a novel TZD-derivative, 9, in which deuterium incorporation at the chiral center was strategically employed to enhance stereoisomeric stability while maintaining the desired pharmacological profile. In vitro, compound 9 displayed robust activity, with an EC50 of 0.32 ± 0.04 μM in HEK293 cells. Pharmacokinetic analysis revealed a Cmax of 1693 ± 339 ng/mL and an AUC0-24h of 8711 ± 871 ng∙h/mL. Furthermore, compound 9 demonstrated superior therapeutic efficacy in a mouse model of NASH. These findings suggest that the compound 9 represents a promising therapeutic candidate for NASH.
{"title":"Exploring the therapeutic potential of deuterated PPARγ agonists for NASH","authors":"Xudong Pang , Dawei Cui , Ruifeng Liu , Binhua Lv , Cheng-Yun Wang","doi":"10.1016/j.bmcl.2025.130489","DOIUrl":"10.1016/j.bmcl.2025.130489","url":null,"abstract":"<div><div>NASH represents an increasingly prevalent chronic liver disease, and TZDs are investigated as a potential therapeutic strategy. However, the inherent enolic structure of TZDs leads to enantiomeric instability and racemization, often requiring their use as racemic mixtures. We here report the development of a novel TZD-derivative, <strong>9</strong>, in which deuterium incorporation at the chiral center was strategically employed to enhance stereoisomeric stability while maintaining the desired pharmacological profile. In vitro, compound <strong>9</strong> displayed robust activity, with an EC<sub>50</sub> of 0.32 ± 0.04 μM in HEK293 cells. Pharmacokinetic analysis revealed a C<sub>max</sub> of 1693 ± 339 ng/mL and an AUC<sub>0-24h</sub> of 8711 ± 871 ng∙h/mL. Furthermore, compound <strong>9</strong> demonstrated superior therapeutic efficacy in a mouse model of NASH. These findings suggest that the compound <strong>9</strong> represents a promising therapeutic candidate for NASH.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130489"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647004","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}
Pub Date : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.bmcl.2025.130501
Yanlei Su , Yujia Wang , Jianyuan Zhao , Keyu Guo , Xuhong Duan , Honghai Wu , Dianxing Sun , Jing Zhang , Shan Cen
Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential via RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.1) and a novel isoflavone analog (Comp.2), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. In vitro assays demonstrated that Comp.1 exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.2. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.1: 0.838 probability) and CYP3A4 inhibition (>0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.
{"title":"Identification of flavonoid-based small molecule inhibitors with dual-targeting capability against RdRp and Mpro of SARS-CoV-2","authors":"Yanlei Su , Yujia Wang , Jianyuan Zhao , Keyu Guo , Xuhong Duan , Honghai Wu , Dianxing Sun , Jing Zhang , Shan Cen","doi":"10.1016/j.bmcl.2025.130501","DOIUrl":"10.1016/j.bmcl.2025.130501","url":null,"abstract":"<div><div>Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential <em>via</em> RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.<strong>1</strong>) and a novel isoflavone analog (Comp.<strong>2</strong>), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. <em>In vitro</em> assays demonstrated that Comp.<strong>1</strong> exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.<strong>2</strong>. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.<strong>1</strong>: 0.838 probability) and CYP3A4 inhibition (>0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130501"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719923","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}
Pub Date : 2026-03-01Epub Date: 2025-12-18DOI: 10.1016/j.bmcl.2025.130509
Le Thi Thao , Hwa Kyung Kim , Nguyen Phuong Ngan , Bui Quang Cuong , Dao Thi Kim Oanh , Do Thi Mai Dung , Da Hyeon Kang , Ha Young Kim , Eun Hye Song , Jong Soon Kang , Duong Tien Anh , Truong Thanh Tung , Sang-Bae Han , Nguyen-Hai Nam
Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (4a-e, 7a-i, and 10a-e) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The 4a-e series emerged as the most potent HDAC inhibitors, with IC50 values of 0.33–0.87 μM, led by 4a (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that 4b (6-CH3) and 4c (7-CH3) were the most effective, achieving IC50 values of 0.93–1.34 μM in HCT116 and 1.79–2.08 μM in SW620. In the 7a-i series, compounds 7b (6-CH3), 7d (6-Cl), and particularly 7f (7-F) demonstrated notable cytotoxicity with IC50 values of 1.14–3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (7g, 7i) or the unsubstituted analog 7a led to markedly reduced activity (> 4.5 μM). The 10a-e series was significantly less active, and 10e (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC50 = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that 4c and 7f induced G2/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight 4a-c and 7f as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.
{"title":"Novel 2-mercaptoquinazolinone N-hydroxycinnamamides as histone deacetylase inhibitors: design, synthesis, and anticancer evaluation","authors":"Le Thi Thao , Hwa Kyung Kim , Nguyen Phuong Ngan , Bui Quang Cuong , Dao Thi Kim Oanh , Do Thi Mai Dung , Da Hyeon Kang , Ha Young Kim , Eun Hye Song , Jong Soon Kang , Duong Tien Anh , Truong Thanh Tung , Sang-Bae Han , Nguyen-Hai Nam","doi":"10.1016/j.bmcl.2025.130509","DOIUrl":"10.1016/j.bmcl.2025.130509","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (<strong>4a-e</strong>, <strong>7a-i</strong>, and <strong>10a-e</strong>) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The <strong>4a-e</strong> series emerged as the most potent HDAC inhibitors, with IC<sub>50</sub> values of 0.33–0.87 μM, led by <strong>4a</strong> (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that <strong>4b</strong> (6-CH<sub>3</sub>) and <strong>4c</strong> (7-CH<sub>3</sub>) were the most effective, achieving IC<sub>50</sub> values of 0.93–1.34 μM in HCT116 and 1.79–2.08 μM in SW620. In the <strong>7a-i</strong> series, compounds <strong>7b</strong> (6-CH<sub>3</sub>), <strong>7d</strong> (6-Cl), and particularly <strong>7f</strong> (7-F) demonstrated notable cytotoxicity with IC<sub>50</sub> values of 1.14–3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (<strong>7g</strong>, <strong>7i</strong>) or the unsubstituted analog <strong>7a</strong> led to markedly reduced activity (> 4.5 μM). The <strong>10a-e</strong> series was significantly less active, and <strong>10e</strong> (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC<sub>50</sub> = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that <strong>4c</strong> and <strong>7f</strong> induced G<sub>2</sub>/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight <strong>4a-c</strong> and <strong>7f</strong> as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130509"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800137","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}
Pub Date : 2026-03-01Epub Date: 2025-11-27DOI: 10.1016/j.bmcl.2025.130482
Yanhui Yi , Yupei Sun , Xiangyang Zhang , Jianzeng Xin , Feng Zhao , Wei Zhu , Sheng Liu
Liver cancer represents a major global health challenge, significantly impacting populations both in China and worldwide. Alpinetin (ALP), extracted from the ginger plant cardamom, has been shown to possess significant anti-liver cancer activity. However, its solubility and mechanism of action remain unclear, hindering its further development and application. Heat shock protein 70 (HSP70) has been proven to be a potential target for the treatment of liver cancer. Based on rational drug design principles, ALP was conjugated with specific pharmacophores through oxime linkages to yield novel compounds, aiming to reduce toxicity and enhanced activity. Thus, representative compounds 1a and 1b were obtained. Then, the preliminary mechanism of action was further investigated. Western blot analysis results indicate that compounds 1a and 1b could inhibit the expression of HSP70 protein in HepG2 liver cancer cells. Cell apoptosis data indicate that the synthesized compounds exert anticancer activity by inducing apoptosis. Therefore, this study suggests that ALP and its derivatives may become promising drugs for exerting anti liver cancer effects by regulating the expression of HSP70 protein.
{"title":"Design, synthesis, and activity evaluation of alpinetin derivatives as potential anti-liver cancer drugs","authors":"Yanhui Yi , Yupei Sun , Xiangyang Zhang , Jianzeng Xin , Feng Zhao , Wei Zhu , Sheng Liu","doi":"10.1016/j.bmcl.2025.130482","DOIUrl":"10.1016/j.bmcl.2025.130482","url":null,"abstract":"<div><div>Liver cancer represents a major global health challenge, significantly impacting populations both in China and worldwide. Alpinetin (ALP), extracted from the ginger plant cardamom, has been shown to possess significant anti-liver cancer activity. However, its solubility and mechanism of action remain unclear, hindering its further development and application. Heat shock protein 70 (HSP70) has been proven to be a potential target for the treatment of liver cancer. Based on rational drug design principles, ALP was conjugated with specific pharmacophores through oxime linkages to yield novel compounds, aiming to reduce toxicity and enhanced activity. Thus, representative compounds 1a and 1b were obtained. Then, the preliminary mechanism of action was further investigated. Western blot analysis results indicate that compounds 1a and 1b could inhibit the expression of HSP70 protein in HepG2 liver cancer cells. Cell apoptosis data indicate that the synthesized compounds exert anticancer activity by inducing apoptosis. Therefore, this study suggests that ALP and its derivatives may become promising drugs for exerting anti liver cancer effects by regulating the expression of HSP70 protein.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130482"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627313","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}
Pub Date : 2026-03-01Epub Date: 2025-12-05DOI: 10.1016/j.bmcl.2025.130498
Mevlüt Akdağ , Merve Güneş Çam , Derya Ergen , Yeliz Demir , Şükrü Beydemir , Azime Berna Özçelik
Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway via aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using in vitro kinetic assays. Among the tested molecules, compound 4, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with Ki values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.
{"title":"Synthesis of new Pyridazinone derivatives and their dual inhibitory activity on aldose reductase and α-glucosidase","authors":"Mevlüt Akdağ , Merve Güneş Çam , Derya Ergen , Yeliz Demir , Şükrü Beydemir , Azime Berna Özçelik","doi":"10.1016/j.bmcl.2025.130498","DOIUrl":"10.1016/j.bmcl.2025.130498","url":null,"abstract":"<div><div>Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway <em>via</em> aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using <em>in vitro</em> kinetic assays. Among the tested molecules, compound <strong>4</strong>, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with K<sub>i</sub> values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130498"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699488","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}
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