Pub Date : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub Date: 2025-10-19DOI: 10.1016/j.bmcl.2025.130439
Danqing Li , Yumiao Zhen , Ran Tang , Boying Wang , Haijing Zhong , Xiaojian Jiang , Ying-Yeung Yeung
The cytotoxicity of α-exo-methylene-lactones has been extensively studied. However, further study of the α-exo-methylene-lactones for anticancer application was hampered primarily by its poor selectivity and solubility. In the present work, a series of α-exo-methylene-selenolactone derivatives bearing amine substituent, selenium functionality and quaternary carbon center were synthesized and evaluated for their anticancer activities. The most potent compound, 2d, was about 9-fold more selective for cancer cells than normal cells. Moreover, 2d significantly inhibited tumor growth in mouse xenograft model and had no observable toxic effect.
{"title":"Synthesis and antitumor activities of quaternary carbon-containing selenolactones","authors":"Danqing Li , Yumiao Zhen , Ran Tang , Boying Wang , Haijing Zhong , Xiaojian Jiang , Ying-Yeung Yeung","doi":"10.1016/j.bmcl.2025.130439","DOIUrl":"10.1016/j.bmcl.2025.130439","url":null,"abstract":"<div><div>The cytotoxicity of α-<em>exo</em>-methylene-lactones has been extensively studied. However, further study of the α-<em>exo</em>-methylene-lactones for anticancer application was hampered primarily by its poor selectivity and solubility. In the present work, a series of α-<em>exo</em>-methylene-selenolactone derivatives bearing amine substituent, selenium functionality and quaternary carbon center were synthesized and evaluated for their anticancer activities. The most potent compound, <strong>2d</strong>, was about 9-fold more selective for cancer cells than normal cells. Moreover, <strong>2d</strong> significantly inhibited tumor growth in mouse xenograft model and had no observable toxic effect.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130439"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342480","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 : 2026-02-01Epub Date: 2025-11-07DOI: 10.1016/j.bmcl.2025.130467
Kobeom Seo , Mijin Jeon , Ju Eun Han , Jinwon Hong , Do Hyeon Kim , Jung Hwan Choi , Seo Yun Jung , Kyeong-Man Kim , Dong Hyun Kim , Jong Hoon Ryu , Jae Yeol Lee
Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α2C adrenoceptor (AR) has emerged as a promising strategy to overcome these limitations. Here, a series of benzoxazole and oxalamide derivatives were designed, synthesized, and biologically evaluated as potential antidepressants targeting α2C AR. Among them, 11e (KMCA-0011), 21b (KMCA-0002), and 21e (KMCA-0028) exhibited the highest binding affinity. Molecular docking studies provided a rationale for the differences in their binding affinities. These compounds demonstrated antagonistic activity by inhibiting ERK phosphorylation without agonistic effects. In a maternal separation (MS) mouse model, all three compounds significantly alleviated depressive-like behaviors, with 11e (KMCA-0011) and 21e (KMCA-0028) showing the most consistent efficacy. Mechanistically, 11e (KMCA-0011) increased hippocampal brain-derived neurotrophic factor (BDNF) levels and restored corticosterone-induced impairments in long-term potentiation (LTP), indicating modulation of synaptic plasticity. Additionally, 11e (KMCA-0011) and 21e (KMCA-0028) displayed favorable ADME profiles, including high plasma stability and minimal CYP inhibition. Given the predicted limited blood–brain barrier (BBB) permeability of 21e (KMCA-0028), these results collectively identify 11e (KMCA-0011) as a promising lead compound that demonstrates robust antidepressant-like activity, likely mediated through α2C AR antagonism and BDNF-dependent neuroplastic mechanisms.
{"title":"α2C Adrenoceptor antagonist KMCA-0011 alleviated depressive-like behaviors in a maternal separation mouse model","authors":"Kobeom Seo , Mijin Jeon , Ju Eun Han , Jinwon Hong , Do Hyeon Kim , Jung Hwan Choi , Seo Yun Jung , Kyeong-Man Kim , Dong Hyun Kim , Jong Hoon Ryu , Jae Yeol Lee","doi":"10.1016/j.bmcl.2025.130467","DOIUrl":"10.1016/j.bmcl.2025.130467","url":null,"abstract":"<div><div>Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α<sub>2C</sub> adrenoceptor (AR) has emerged as a promising strategy to overcome these limitations. Here, a series of benzoxazole and oxalamide derivatives were designed, synthesized, and biologically evaluated as potential antidepressants targeting α<sub>2C</sub> AR. Among them, <strong>11e</strong> (KMCA-0011), <strong>21b</strong> (KMCA-0002), and <strong>21e</strong> (KMCA-0028) exhibited the highest binding affinity. Molecular docking studies provided a rationale for the differences in their binding affinities. These compounds demonstrated antagonistic activity by inhibiting ERK phosphorylation without agonistic effects. In a maternal separation (MS) mouse model, all three compounds significantly alleviated depressive-like behaviors, with <strong>11e</strong> (KMCA-0011) and <strong>21e</strong> (KMCA-0028) showing the most consistent efficacy. Mechanistically, <strong>11e</strong> (KMCA-0011) increased hippocampal brain-derived neurotrophic factor (BDNF) levels and restored corticosterone-induced impairments in long-term potentiation (LTP), indicating modulation of synaptic plasticity. Additionally, <strong>11e</strong> (KMCA-0011) and <strong>21e</strong> (KMCA-0028) displayed favorable ADME profiles, including high plasma stability and minimal CYP inhibition. Given the predicted limited blood–brain barrier (BBB) permeability of <strong>21e</strong> (KMCA-0028), these results collectively identify <strong>11e</strong> (KMCA-0011) as a promising lead compound that demonstrates robust antidepressant-like activity, likely mediated through α<sub>2C</sub> AR antagonism and BDNF-dependent neuroplastic mechanisms.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130467"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476509","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}
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":"2026-02-01","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 : 2026-02-01Epub 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":"2026-02-01","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}
Pub Date : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub Date: 2025-11-05DOI: 10.1016/j.bmcl.2025.130463
Fernando Banales-Mejia , Emily M. Dieter , Kyler J. Radmall , Glenna W. Foight , Douglas M. Fowler , Dustin J. Maly
Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which involve the pre-localization of two interacting protein components that can be disrupted with a small molecule, are complementary to more commonly used chemically-inducible dimerization (CID) systems. However, fewer CDP systems have been developed, and the genetically-encoded protein components have not been as optimized for intracellular applications. Here, we describe a transcriptional activation reporter assay for screening the intracellular interaction between the 21-amino acid peptide ANR and HCVp NS3a, which are the genetically-encoded components of a CDP system that utilizes clinically-approved antiviral drugs. We used this assay to screen a library of single amino acid substitution ANR variants and identified several that increase the intracellular interaction between ANR and NS3a. By combining affinity-optimized single substitutions, we achieved improved transcriptional activation and engineered an autoinhibited signaling switch with low basal activity. Together, our study describes a functional assay for screening genetically-encoded CDP components and a more optimized version of ANR for intracellular applications.
{"title":"Identification of affinity-optimized peptide binders of a viral protease for chemical genetic applications","authors":"Fernando Banales-Mejia , Emily M. Dieter , Kyler J. Radmall , Glenna W. Foight , Douglas M. Fowler , Dustin J. Maly","doi":"10.1016/j.bmcl.2025.130463","DOIUrl":"10.1016/j.bmcl.2025.130463","url":null,"abstract":"<div><div>Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which involve the pre-localization of two interacting protein components that can be disrupted with a small molecule, are complementary to more commonly used chemically-inducible dimerization (CID) systems. However, fewer CDP systems have been developed, and the genetically-encoded protein components have not been as optimized for intracellular applications. Here, we describe a transcriptional activation reporter assay for screening the intracellular interaction between the 21-amino acid peptide ANR and HCVp NS3a, which are the genetically-encoded components of a CDP system that utilizes clinically-approved antiviral drugs. We used this assay to screen a library of single amino acid substitution ANR variants and identified several that increase the intracellular interaction between ANR and NS3a. By combining affinity-optimized single substitutions, we achieved improved transcriptional activation and engineered an autoinhibited signaling switch with low basal activity. Together, our study describes a functional assay for screening genetically-encoded CDP components and a more optimized version of ANR for intracellular applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130463"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457031","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}
In the context of rapidly developing resistance caused by mutations in genes that control oncogenic pathways and cancer cell survival, as well as to known and widely accessible antitumor drugs, combined strategies are critical as a modern approach to cancer therapy. The in vitro results from a study of several long-chain N-alkylimidazole derivatives, combined with the known anticancer drugs doxorubicin and cisplatin, using cell lines of chronic myeloid leukemia K562, neuroblastoma SK-N-DZ, and mammary gland adenocarcinoma MCF7, show that the imidazolium-based ionic liquids 1-dodecyl-3-methylimidazolium chloride (IMC12C1-Cl), 1-dodecyloxycarbonylmethyl-3-methylimidazolium chloride (IMC1CH2COOC12-Cl), and, to a lesser extent, lysosomotropic detergent 1-dodecylimidazole (IMC12) consistently stand out as the most promising across all cell lines. IMC12C1-Cl demonstrated significant reductions in cisplatin and doxorubicin doses, along with enhanced cytotoxic effects, in both K562 and SK-N-DZ cells, with DRI values of 4.36 μM for cisplatin and 15.00 μM for doxorubicin. IMC1CH2COOC12-Cl showed high DRI and synergism in MCF7 cells and moderate activity in SK-N-DZ cells. IMC12C1-Cl and IMC1CH2COOC12-Cl appear to be promising candidates for the development and evaluation of their combinatorial anticancer effects.
{"title":"Investigation of the combinatorial anticancer effects of imidazolium-based ionic liquids and lysosomotropic detergents with cisplatin and doxorubicin","authors":"Anastasiia Gryniukova , Sergiy Rogalsky , Petro Borysko , Diana Hodyna , Vasyl Kovalishyn , Larysa Metelytsia","doi":"10.1016/j.bmcl.2025.130474","DOIUrl":"10.1016/j.bmcl.2025.130474","url":null,"abstract":"<div><div>In the context of rapidly developing resistance caused by mutations in genes that control oncogenic pathways and cancer cell survival, as well as to known and widely accessible antitumor drugs, combined strategies are critical as a modern approach to cancer therapy. The <em>in vitro</em> results from a study of several long-chain N-alkylimidazole derivatives, combined with the known anticancer drugs doxorubicin and cisplatin, using cell lines of chronic myeloid leukemia K562, neuroblastoma SK-N-DZ, and mammary gland adenocarcinoma MCF7, show that the imidazolium-based ionic liquids 1-dodecyl-3-methylimidazolium chloride (IMC<sub>12</sub>C<sub>1</sub>-Cl), 1-dodecyloxycarbonylmethyl-3-methylimidazolium chloride (IMC<sub>1</sub>CH<sub>2</sub>COOC<sub>12</sub>-Cl), and, to a lesser extent, lysosomotropic detergent 1-dodecylimidazole (IMC<sub>12</sub>) consistently stand out as the most promising across all cell lines. IMC<sub>12</sub>C<sub>1</sub>-Cl demonstrated significant reductions in cisplatin and doxorubicin doses, along with enhanced cytotoxic effects, in both K562 and SK-N-DZ cells, with DRI values of 4.36 μM for cisplatin and 15.00 μM for doxorubicin. IMC<sub>1</sub>CH<sub>2</sub>COOC<sub>12</sub>-Cl showed high DRI and synergism in MCF7 cells and moderate activity in SK-N-DZ cells. IMC<sub>12</sub>C<sub>1</sub>-Cl and IMC<sub>1</sub>CH<sub>2</sub>COOC<sub>12</sub>-Cl appear to be promising candidates for the development and evaluation of their combinatorial anticancer effects.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130474"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538251","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}
Gold nanorods (GNRs) can perform photothermal energy conversion by absorbing near-infrared (NIR) light and converting it to heat, and are therefore promising for applications in photothermal cancer therapy. However, to synthesize these nanorods, the highly cytotoxic compound cetyltrimethylammonium bromide (CTAB) is required. In the present study, to overcome this difficulty, we developed a method for synthesizing CTAB-free nanocrystals in the form of gold nanoworms (GNWs) using a self-assembling peptide exhibiting a positively-charged nuclear localization signal (NLS) sequence. We investigated the photothermal conversion performance of the GNWs and their ability to induce cell death under NIR irradiation. Based on transmission electron microscopy observations, the NLS-GNWs were determined to be approximately 80 nm in length and 9 nm in width. Their photothermal conversion efficiency was estimated to be 0.27 ± 0.06. Interestingly, in the absence of NLS-GNWs, following three cycles of NIR light exposure for 5 min at an intensity of 5 W/cm2 separated by 10 min intervals, no significant change in cytotoxicity of HeLa cells was observed compared with the control. However, in the presence of NLS-GNWs, the cell viability after the first, second and third cycles was approximately 25 %, 18 % and 10 %, respectively. The intracellular localization of NLS-GNWs was also investigated using fluorescein labelled-NLS-GNWs, and it was found that many of the GNWs were present at the nuclei of the HeLa cells. The positively-charged NLS-GNWs are thought to have been attracted to the relatively acidic surfaces of the cancer cells.
{"title":"Worm-like gold nanocrystals fabricated using a self-assembling peptide and inducing cell death upon exposure to near infrared light","authors":"Soo-Ang Ahn , Kazutoshi Ishida , Ryuki Watanabe , Takahito Imai , Masayuki Yamasaki , Kin-ya Tomizaki","doi":"10.1016/j.bmcl.2025.130472","DOIUrl":"10.1016/j.bmcl.2025.130472","url":null,"abstract":"<div><div>Gold nanorods (GNRs) can perform photothermal energy conversion by absorbing near-infrared (NIR) light and converting it to heat, and are therefore promising for applications in photothermal cancer therapy. However, to synthesize these nanorods, the highly cytotoxic compound cetyltrimethylammonium bromide (CTAB) is required. In the present study, to overcome this difficulty, we developed a method for synthesizing CTAB-free nanocrystals in the form of gold nanoworms (GNWs) using a self-assembling peptide exhibiting a positively-charged nuclear localization signal (NLS) sequence. We investigated the photothermal conversion performance of the GNWs and their ability to induce cell death under NIR irradiation. Based on transmission electron microscopy observations, the NLS-GNWs were determined to be approximately 80 nm in length and 9 nm in width. Their photothermal conversion efficiency was estimated to be 0.27 ± 0.06. Interestingly, in the absence of NLS-GNWs, following three cycles of NIR light exposure for 5 min at an intensity of 5 W/cm<sup>2</sup> separated by 10 min intervals, no significant change in cytotoxicity of HeLa cells was observed compared with the control. However, in the presence of NLS-GNWs, the cell viability after the first, second and third cycles was approximately 25 %, 18 % and 10 %, respectively. The intracellular localization of NLS-GNWs was also investigated using fluorescein labelled-NLS-GNWs, and it was found that many of the GNWs were present at the nuclei of the HeLa cells. The positively-charged NLS-GNWs are thought to have been attracted to the relatively acidic surfaces of the cancer cells.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130472"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511470","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 : 2026-02-01Epub 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":"2026-02-01","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}
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