Millions of people are being affected by chronic pain, and it is insufficiently addressed by the current classes of analgesics. Nav1.7 channels have emerged as promising targets in this pain context since their systemic inhibition can cancel pain perception altogether. In this work, we report a novel, O-alkylated piperine derivative 3ag as an inhibitor of Nav1.7 channels with an IC50 of 3.10 μM. Furthermore, this molecule displayed an oral analgesic efficacy in a CFA inflammatory pain model at 10 mg/kg. Based on our findings, this molecule could be used as a starting point for the development of new Nav1.7-specific blockers for anti-nociception.
{"title":"Discovery of O-alkylated derivative of piperine as Nav1.7 channel inhibitor for the treatment of pain","authors":"Vikrant Nawal Vikram , Madhavi Ranawat , Aditya Singh , Shiv Kumar , Ashutosh Sharma , Shivani Yadav , Vikash Kumar , Aravind Singh Kshatri , Tadigoppula Narender","doi":"10.1016/j.bmcl.2025.130461","DOIUrl":"10.1016/j.bmcl.2025.130461","url":null,"abstract":"<div><div>Millions of people are being affected by chronic pain, and it is insufficiently addressed by the current classes of analgesics. Nav1.7 channels have emerged as promising targets in this pain context since their systemic inhibition can cancel pain perception altogether. In this work, we report a novel, O-alkylated piperine derivative <strong>3ag</strong> as an inhibitor of Nav1.7 channels with an IC<sub>50</sub> of 3.10 μM. Furthermore, this molecule displayed an oral analgesic efficacy in a CFA inflammatory pain model at 10 mg/kg. Based on our findings, this molecule could be used as a starting point for the development of new Nav1.7-specific blockers for anti-nociception.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130461"},"PeriodicalIF":2.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457067","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 : 2025-11-03DOI: 10.1016/j.bmcl.2025.130460
Longfei Zhang, Hossam Hammouda Nada Hammouda, Moustafa T. Gabr
Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeutic target. To overcome the limited availability of small molecule CHI3L1 inhibitors, we established a surface plasmon resonance (SPR)–based high-throughput screening platform and applied it to a focused chemical library of small molecules. Primary screening identified seven hits, with compounds 1–4 and 1–7 validated as CHI3L1 binders (Kd = 10.4 ± 1.0 μM and 7.40 ± 0.78 μM, respectively). Both compounds disrupted the CHI3L1–galectin-3 interaction in AlphaLISA assays and engaged the CHI3L1 binding pocket in docking and molecular dynamics (MD) simulations. Importantly, functional evaluation in a multicellular 3D glioblastoma (GBM) spheroid model demonstrated that compound 1–7 potently reduced spheroid viability and inhibited STAT3 phosphorylation, outperforming both compound 1–4 and the known CHI3L1–STAT3 disruptor hygromycin B (HB). These findings validate SPR as a robust primary screening platform for CHI3L1 and demonstrate that the identified small molecule binders exert functional activity in a physiologically relevant multicellular GBM spheroid model.
{"title":"Discovery of small molecule CHI3L1 inhibitors by SPR-based high-throughput screening","authors":"Longfei Zhang, Hossam Hammouda Nada Hammouda, Moustafa T. Gabr","doi":"10.1016/j.bmcl.2025.130460","DOIUrl":"10.1016/j.bmcl.2025.130460","url":null,"abstract":"<div><div>Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeutic target. To overcome the limited availability of small molecule CHI3L1 inhibitors, we established a surface plasmon resonance (SPR)–based high-throughput screening platform and applied it to a focused chemical library of small molecules. Primary screening identified seven hits, with compounds <strong>1–4</strong> and <strong>1–7</strong> validated as CHI3L1 binders (<em>Kd</em> = 10.4 ± 1.0 μM and 7.40 ± 0.78 μM, respectively). Both compounds disrupted the CHI3L1–galectin-3 interaction in AlphaLISA assays and engaged the CHI3L1 binding pocket in docking and molecular dynamics (MD) simulations. Importantly, functional evaluation in a multicellular 3D glioblastoma (GBM) spheroid model demonstrated that compound <strong>1–7</strong> potently reduced spheroid viability and inhibited STAT3 phosphorylation, outperforming both compound <strong>1–4</strong> and the known CHI3L1–STAT3 disruptor hygromycin B (HB). These findings validate SPR as a robust primary screening platform for CHI3L1 and demonstrate that the identified small molecule binders exert functional activity in a physiologically relevant multicellular GBM spheroid model.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130460"},"PeriodicalIF":2.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450325","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 : 2025-11-01DOI: 10.1016/j.bmcl.2025.130456
Jingmei Yang, Ran Friedman
The Ba/F3 cell line is a widely used model in kinase drug development. Such cells are transformed to depend on a certain kinase for proliferation, and the use of an inhibitor of the kinase thus prevents their growth. We used Ba/F3 cells that expressed mutated FLT3 (FLT3-ITD), a known drug target in acute myeloid leukaemia (AML), to study drug resistance against two potent and selective inhibitors (gilteritinib and FF-10101). The cells could be made resistant to the drugs in concentrations that are similar to those in the plasma of patients, but this often required multiple secondary mutations. Several novel inhibitors, designed to be active against FLT3 mutants were tested but could not inhibit the growth of the resistant Ba/F3 cells. Several hitherto unidentified mutations in FLT3 were discovered that lead to drug resistance. These mutations were further studied using computational tools in order to understand how they lead to drug resistance. The discovery of novel mutations is significant since few patients were tested upon relapse due to lack of therapeutic options. Finally, we discuss the pros and cons of the Ba/F3 cell lines in the context of AML where patients express FLT3-ITD mutations in comparison with other cell lines, when the aim is development of drugs that overcome resistance.
{"title":"Strengths and limitations of Ba/F3 cells in modelling FLT3-driven AML resistance","authors":"Jingmei Yang, Ran Friedman","doi":"10.1016/j.bmcl.2025.130456","DOIUrl":"10.1016/j.bmcl.2025.130456","url":null,"abstract":"<div><div>The Ba/F3 cell line is a widely used model in kinase drug development. Such cells are transformed to depend on a certain kinase for proliferation, and the use of an inhibitor of the kinase thus prevents their growth. We used Ba/F3 cells that expressed mutated FLT3 (FLT3-ITD), a known drug target in acute myeloid leukaemia (AML), to study drug resistance against two potent and selective inhibitors (gilteritinib and FF-10101). The cells could be made resistant to the drugs in concentrations that are similar to those in the plasma of patients, but this often required multiple secondary mutations. Several novel inhibitors, designed to be active against FLT3 mutants were tested but could not inhibit the growth of the resistant Ba/F3 cells. Several hitherto unidentified mutations in FLT3 were discovered that lead to drug resistance. These mutations were further studied using computational tools in order to understand how they lead to drug resistance. The discovery of novel mutations is significant since few patients were tested upon relapse due to lack of therapeutic options. Finally, we discuss the pros and cons of the Ba/F3 cell lines in the context of AML where patients express FLT3-ITD mutations in comparison with other cell lines, when the aim is development of drugs that overcome resistance.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130456"},"PeriodicalIF":2.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436735","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 : 2025-11-01DOI: 10.1016/j.bmcl.2025.130458
Deok-Mo Yang , Yeo Wool Kang , Kwonwoo Kim , Suk-Ho Lee , Taegwon Oh , Kye Jung Shin , Myung Jin Kim , Tae-Hwe Heo , Ikyon Kim
The immune system plays a critical role in cancer control, but tumor cells often evade immune responses by exploiting inhibitory molecules like PD-1/PD-L1. Monoclonal antibodies targeting PD-1/PD-L1 interaction blockade have shown remarkable success in reactivating T-cell function in various advanced cancers, but they face limitations such as long half-life and immune-related adverse events (irAEs). In this study, we identified a new class of indoline-based scaffold through molecular docking analysis and synthesized derivatives, identifying compound 31 with an IC50 of 0.89 nM in FRET assay. Compound 31 showed less than 50 % inhibition against CYP and hERG, and demonstrated moderate liver microsomal stability in mice. These results suggest that indoline derivatives may serve as potential PD-L1 inhibitors and warrant further investigation.
{"title":"Discovery of novel indoline derivatives as potent small molecule PD-L1 inhibitors","authors":"Deok-Mo Yang , Yeo Wool Kang , Kwonwoo Kim , Suk-Ho Lee , Taegwon Oh , Kye Jung Shin , Myung Jin Kim , Tae-Hwe Heo , Ikyon Kim","doi":"10.1016/j.bmcl.2025.130458","DOIUrl":"10.1016/j.bmcl.2025.130458","url":null,"abstract":"<div><div>The immune system plays a critical role in cancer control, but tumor cells often evade immune responses by exploiting inhibitory molecules like PD-1/PD-L1. Monoclonal antibodies targeting PD-1/PD-L1 interaction blockade have shown remarkable success in reactivating T-cell function in various advanced cancers, but they face limitations such as long half-life and immune-related adverse events (irAEs). In this study, we identified a new class of indoline-based scaffold through molecular docking analysis and synthesized derivatives, identifying compound <strong>31</strong> with an IC<sub>50</sub> of 0.89 nM in FRET assay. Compound <strong>31</strong> showed less than 50 % inhibition against CYP and hERG, and demonstrated moderate liver microsomal stability in mice. These results suggest that indoline derivatives may serve as potential PD-L1 inhibitors and warrant further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130458"},"PeriodicalIF":2.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436725","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 : 2025-10-30DOI: 10.1016/j.bmcl.2025.130457
Hannah L. Bolt , Marcel Kaiser , Yu Luo , Fionnuala T. Lundy , Libbi Moon , Ronald N. Zuckermann , Paul W. Denny , Steven L. Cobb
Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African sleeping sickness. Often treatments for protozan parasites are limited in their efficacy and drug resistance is an emerging problem. The current efforts to develop new treatments for the aforementioned diseases have been met with limited success and as such novel compound classes for development are being actively sought. Peptoids are peptidomimetics that have showed promise as antimicrobial agents but their application in the field of vector-borne parasitic diseases is highly underdeveloped. Herein, a library of over 50 peptoids containing a wide variety of chemical functionalities has been prepared and biologically evaluated against a range of protozoan parasitic targets. Selected members of the peptoid library were found to have potent anti-parasitic activity and good selectivity indices (SI). For example, peptoid 29 [NamyNspeNspe)(NhArgNspeNspe)]2 had an IC50 of 0.05 μM against Plasmodium falciparum and a SI > 100.
{"title":"Bioactive peptoids against vector-borne parasitic diseases","authors":"Hannah L. Bolt , Marcel Kaiser , Yu Luo , Fionnuala T. Lundy , Libbi Moon , Ronald N. Zuckermann , Paul W. Denny , Steven L. Cobb","doi":"10.1016/j.bmcl.2025.130457","DOIUrl":"10.1016/j.bmcl.2025.130457","url":null,"abstract":"<div><div>Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African sleeping sickness. Often treatments for protozan parasites are limited in their efficacy and drug resistance is an emerging problem. The current efforts to develop new treatments for the aforementioned diseases have been met with limited success and as such novel compound classes for development are being actively sought. Peptoids are peptidomimetics that have showed promise as antimicrobial agents but their application in the field of vector-borne parasitic diseases is highly underdeveloped. Herein, a library of over 50 peptoids containing a wide variety of chemical functionalities has been prepared and biologically evaluated against a range of protozoan parasitic targets. Selected members of the peptoid library were found to have potent anti-parasitic activity and good selectivity indices (SI). For example, peptoid <strong>29</strong> [<em>N</em>amy<em>N</em>spe<em>N</em>spe)(<em>N</em>hArg<em>N</em>spe<em>N</em>spe)]<sub>2</sub> had an IC<sub>50</sub> of 0.05 μM against <em>Plasmodium falciparum</em> and a SI > 100.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130457"},"PeriodicalIF":2.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426408","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 : 2025-10-30DOI: 10.1016/j.bmcl.2025.130459
Nicole Wandrey , Jake Boley , Dirce Gómez-Galicia , Mackinzi Hill , Mason Bach , Sidney Gawrych , Mackenzie Hagemeister , Philip A. Cole , Michael A. Moxley , Allen A. Thomas
Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a series of hydantoin indolinone-based AANAT inhibitors, developed as more stable alternatives to a previously reported rhodanine scaffold. Guided by docking studies and prior structure-activity data, we modified four regions of the molecule to improve potency. Substitution at the 5-position of the indolinone ring led to marked increases in activity, with compound 5g (bearing a CH3CO2CH2- substituent) resulting in an IC₅₀ of 1.1 μM—representing a 19-fold improvement over the parent compound. Kinetic mechanism studies were also conducted with respect to acetyl-CoA and serotonin to explore inhibitor binding. These findings establish a promising starting point for the development of more potent AANAT inhibitors as chemical probes for studying melatonin's function.
芳基烷基胺n -乙酰转移酶（AANAT）是褪黑激素生物合成的关键酶，也是昼夜节律的调节剂，与季节性情感障碍（SAD）等情绪障碍有潜在关联。我们报道了一系列以吲哚啉酮为基础的AANAT抑制剂，作为先前报道的罗丹宁支架更稳定的替代品。在对接研究和先前的结构活性数据的指导下，我们修改了分子的四个区域以提高效力。吲哚酮环5位的取代导致活性显着增加，化合物5g（含有CH3CO2CH2-取代基）导致IC₅0为1.1 μ m -比母体化合物提高了19倍。还进行了关于乙酰辅酶a和血清素的动力学机制研究，以探索抑制剂的结合。这些发现为开发更有效的AANAT抑制剂作为研究褪黑激素功能的化学探针奠定了一个有希望的起点。
{"title":"Hydantion indolinones as AANAT inhibitors","authors":"Nicole Wandrey , Jake Boley , Dirce Gómez-Galicia , Mackinzi Hill , Mason Bach , Sidney Gawrych , Mackenzie Hagemeister , Philip A. Cole , Michael A. Moxley , Allen A. Thomas","doi":"10.1016/j.bmcl.2025.130459","DOIUrl":"10.1016/j.bmcl.2025.130459","url":null,"abstract":"<div><div>Arylalkylamine <em>N</em>-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a series of hydantoin indolinone-based AANAT inhibitors, developed as more stable alternatives to a previously reported rhodanine scaffold. Guided by docking studies and prior structure-activity data, we modified four regions of the molecule to improve potency. Substitution at the 5-position of the indolinone ring led to marked increases in activity, with compound <strong>5g</strong> (bearing a CH<sub>3</sub>CO<sub>2</sub>CH<sub>2</sub>- substituent) resulting in an IC₅₀ of 1.1 μM—representing a 19-fold improvement over the parent compound. Kinetic mechanism studies were also conducted with respect to acetyl-CoA and serotonin to explore inhibitor binding. These findings establish a promising starting point for the development of more potent AANAT inhibitors as chemical probes for studying melatonin's function.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130459"},"PeriodicalIF":2.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426338","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}
Tumors remain a leading cause of mortality worldwide, and existing clinical treatments face challenges such as high toxicity, poor efficacy, and multidrug resistance. Natural products have emerged as promising sources for developing anticancer drugs due to their high efficacy and low toxicity. Curcumin, a yellow polyphenolic compound with diverse biological activities (anti-tumor, antiviral, antibacterial, and anti-HIV), is particularly notable for its minimal toxic side effects. However, its clinical application is hindered by low oral bioavailability and instability. To address these limitations, this study designed and synthesized nine novel monocarbonyl curcumin analogs by removing the unstable β-diketone group and introducing ferrocene-based structures with piperidone derivatives. Using ferrocene as a starting material, these asymmetric compounds were synthesized through Vilsmeier and Claisen-Schmidt reactions, followed by structural confirmation using 1H NMR, MS, and 13C NMR. Antitumor activity was evaluated against MCF-7, PC-3, and A549 tumor cells using the CCK-8 method, with curcumin as a control. Notably, several analogs exhibited dramatically enhanced potency. Compound 1a was identified as the most promising derivative, showing 4.7-, 7.4-, and 2.0-fold higher potency than curcumin against A549, PC-3, and MCF-7 cells, respectively (IC₅₀ = 6.11, 5.21, and 10.37 μM vs. 28.92, 38.53, and 20.82 μM for curcumin). These findings provide a foundation for further development of ferrocene-modified curcumin analogs as potential anticancer agents.
{"title":"Ferrocene-modified cyclic asymmetric curcumin analogs: Synthesis and enhanced antitumor activity","authors":"Haotian Xie , Wenjie Xiao , Ruichen Xie , Lifang Xu , Shuhui Ren , Hanfeng Cui","doi":"10.1016/j.bmcl.2025.130446","DOIUrl":"10.1016/j.bmcl.2025.130446","url":null,"abstract":"<div><div>Tumors remain a leading cause of mortality worldwide, and existing clinical treatments face challenges such as high toxicity, poor efficacy, and multidrug resistance. Natural products have emerged as promising sources for developing anticancer drugs due to their high efficacy and low toxicity. Curcumin, a yellow polyphenolic compound with diverse biological activities (anti-tumor, antiviral, antibacterial, and anti-HIV), is particularly notable for its minimal toxic side effects. However, its clinical application is hindered by low oral bioavailability and instability. To address these limitations, this study designed and synthesized nine novel monocarbonyl curcumin analogs by removing the unstable β-diketone group and introducing ferrocene-based structures with piperidone derivatives. Using ferrocene as a starting material, these asymmetric compounds were synthesized through Vilsmeier and Claisen-Schmidt reactions, followed by structural confirmation using <sup>1</sup><em>H</em> NMR, MS, and <sup>13</sup><em>C</em> NMR. Antitumor activity was evaluated against MCF-7, PC-3, and A549 tumor cells using the CCK-8 method, with curcumin as a control. Notably, several analogs exhibited dramatically enhanced potency. Compound <strong>1a</strong> was identified as the most promising derivative, showing 4.7-, 7.4-, and 2.0-fold higher potency than curcumin against A549, PC-3, and MCF-7 cells, respectively (IC₅₀ = 6.11, 5.21, and 10.37 μM vs. 28.92, 38.53, and 20.82 μM for curcumin). These findings provide a foundation for further development of ferrocene-modified curcumin analogs as potential anticancer agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130446"},"PeriodicalIF":2.2,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413910","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 : 2025-10-22DOI: 10.1016/j.bmcl.2025.130442
Yong Wang , Yingchuan Que , Yi Gu , Jia Xia , Yi Dong , Lumin Tang , Shan Mou , Gang Chen
Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (11a) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and 11a effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative 11a emerging as a particularly promising candidate for further development.
{"title":"Late-stage functionalization of Cycloastragenol and anti-inflammatory study","authors":"Yong Wang , Yingchuan Que , Yi Gu , Jia Xia , Yi Dong , Lumin Tang , Shan Mou , Gang Chen","doi":"10.1016/j.bmcl.2025.130442","DOIUrl":"10.1016/j.bmcl.2025.130442","url":null,"abstract":"<div><div>Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (<strong>11a</strong>) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and <strong>11a</strong> effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative <strong>11a</strong> emerging as a particularly promising candidate for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130442"},"PeriodicalIF":2.2,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367242","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 : 2025-10-21DOI: 10.1016/j.bmcl.2025.130440
Xu Hu , Xiaoni Yu , Yutian Zhang , Biao Zhou , Chao Li , Dahong Li , Shengge Li , Xianzhang Huang
Natural β-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of β-carboline, a range of β-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (12a-c, 13a-d, 14a-d, and 15a-d) were evaluated for in vitro cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid 12c exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC50 value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC50 > 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that 12c induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that 12c exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, 12c may represent a promising anti-leukemia agent and warrants further investigation.
{"title":"Enhancement of anticancer potential of novel β-carboline derivatives by ACS81 hybridization","authors":"Xu Hu , Xiaoni Yu , Yutian Zhang , Biao Zhou , Chao Li , Dahong Li , Shengge Li , Xianzhang Huang","doi":"10.1016/j.bmcl.2025.130440","DOIUrl":"10.1016/j.bmcl.2025.130440","url":null,"abstract":"<div><div>Natural <em>β</em>-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of <em>β</em>-carboline, a range of <em>β</em>-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (<strong>12a-c</strong>, <strong>13a-d</strong>, <strong>14a-d</strong>, and <strong>15a-d</strong>) were evaluated for <em>in vitro</em> cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid <strong>12c</strong> exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC<sub>50</sub> value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC<sub>50</sub> > 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that <strong>12c</strong> induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that <strong>12c</strong> exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, <strong>12c</strong> may represent a promising anti-leukemia agent and warrants further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130440"},"PeriodicalIF":2.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353199","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 : 2025-10-21DOI: 10.1016/j.bmcl.2025.130443
En-Jie Zhu , Xing-Sheng Bu , Ying Yue , Yong-Sheng Hou , Jia-Rong Liu , Tharcisse Gatera , Shu-Yang Ni , Tian Chai , Xing-Rong Wang , Jun-Li Yang
Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.
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