ACS Omega最新文献

{"title":"Structural Modeling of NTPDase-Substrate Complexes Preserving Catalytic Experimental Features","authors":"João Victor B. de Moraes,&nbsp;, ,&nbsp;Marcelo D. Polêto,&nbsp;, ,&nbsp;Raissa B. de Castro,&nbsp;, ,&nbsp;Gustavo C. Bressan,&nbsp;, ,&nbsp;Raphael de S Vasconcellos,&nbsp;, ,&nbsp;Jean Sévigny*,&nbsp;, and ,&nbsp;Juliana R. Fietto*,&nbsp;","doi":"10.1021/acsomega.5c04628","DOIUrl":"https://doi.org/10.1021/acsomega.5c04628","url":null,"abstract":"<p >Members of the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family play a pivotal role in hydrolyzing nucleoside triphosphates and diphosphates, modulating purinergic and pyrimidinergic signaling pathways. The NTPDases have therapeutic potential; gaining structural insights into NTPDase-substrate complexes would be valuable for optimizing these enzymes for therapeutic applications. However, such insights remain limited, posing challenges for effective optimization. Molecular docking often fails to capture experimentally characterized substrate conformations, leading to biologically irrelevant models. To address this, we developed a computational strategy that preserves experimentally observed substrate features while leveraging the active site’s conservation across NTPDases. Our method identifies a canonical linear-like substrate conformation encompassing the phosphate tail and nucleobase ring conserved across experimental NTPDase structures. This approach enabled the modeling of <i>Homo sapiens</i> (Hs) NTPDases (HsNTPDase1–8) complexed with ATP, ADP, GTP, GDP, UTP, and UDP, accurately positioning metal ion cofactor and catalytic water molecules. The resulting models offer a reliable framework for studying enzyme–substrate interactions, paving the way for rational enzyme engineering and therapeutic exploration.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"43891–43902"},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c04628","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multi-input Deep Learning Architecture for STAT3 Inhibitor Prediction","authors":"Kairui Liang,&nbsp;, ,&nbsp;Wenling Qin*,&nbsp;, and ,&nbsp;Yonghong Zhang*,&nbsp;","doi":"10.1021/acsomega.5c05380","DOIUrl":"https://doi.org/10.1021/acsomega.5c05380","url":null,"abstract":"<p >Signal transducer and activator of transcription 3 (STAT3) is a critical factor involved in various physiological and oncogenic signaling pathways. Machine learning models are valuable tools for predicting or screening STAT3 inhibitors. However, the predictive performance and interpretability of existing models still require improvement. In this study, we introduce a fingerprint-enhanced graph (FPG) attention network model, which integrates sequence-based fingerprints and structure-based graph representations to predict STAT3 inhibitors. During the feature learning process, the FPG model converts sequence information into a fingerprint vector, while structural information is encoded into a separate vector using a graph attention network module. These two vectors are then concatenated and passed through a multilayer perceptron for molecular activity classification. Among 49 models with various representations and algorithm combinations, the FPG-based model achieved the best predictive performance, with an average area under the curve of 0.897 on the test set. Furthermore, the model outperformed existing prediction models for identifying STAT3 inhibitors. Additionally, fingerprint analysis and attention heatmaps, combined with SHAP algorithms, provided valuable insights into the structure–activity relationship of STAT3 inhibitors, enhancing model interpretability. To facilitate related research and applications, we developed a web service (STAT3 Pro: https://gzliang.cqu.edu.cn/software/Stat3Pro.html) for STAT3 inhibitor prediction.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"44125–44136"},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c05380","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Chemical and Enantioselective Analysis of a New Essential Oil Produced by the Native Andean Species Aiouea dubia (Kunth) Mez from Ecuador","authors":"Katherin Fiallos,&nbsp;, ,&nbsp;Yessenia E. Maldonado,&nbsp;, ,&nbsp;Nixon Cumbicus,&nbsp;, and ,&nbsp;Gianluca Gilardoni*,&nbsp;","doi":"10.1021/acsomega.5c05278","DOIUrl":"https://doi.org/10.1021/acsomega.5c05278","url":null,"abstract":"<p >The present study constitutes the first description of an essential oil, distilled from the leaves of the native Andean species <i>Aiouea dubia</i> (Kunth) Mez. The qualitative and quantitative analyses were carried out through GC–MS and GC-FID respectively, using two columns coated with stationary phases of different polarity. The qualitative composition was determined by comparison of linear retention indices and mass spectra with data from literature, whereas the quantitative composition was obtained through external calibration, calculating the relative response factor of each compound according to the respective combustion enthalpy. Major constituents (≥3.0 on at least one column) of <i>A. dubia</i> EO, on a nonpolar and a polar stationary phase respectively, were germacrene D (12.2%–11.7%), γ-muurolene (7.6%–7.2%), limonene (6.8%–6.2%), δ-cadinene (6.4%–5.9%), cyclosativene (6.0%–5.5%), and (<i>E</i>)-β-caryophyllene (4.4%–4.0%). The enantioselective analysis was also conducted on two different columns, based on β-cyclodextrin as chiral selector. A total of 11 chiral terpenes and terpenoids were analyzed, of which (1<i>S</i>,5<i>S</i>)-(−)-α-pinene and (1<i>R</i>,6<i>S</i>)-(−)-3-carene were enantiomerically pure, whereas the others were observed as scalemic mixtures. Cosmeceutical science could be the main application field for this volatile fraction. In fact, the high content of limonene and (<i>E</i>)-β-caryophyllene suggested that this EO could present antibacterial and anti-inflammatory properties, like other volatile fractions of similar composition.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"44077–44086"},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c05278","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-IPR Fullertube Series C10+10+6n: A Theoretical Prediction","authors":"Kexin Ma,&nbsp;, ,&nbsp;Kai Tan*,&nbsp;, ,&nbsp;Anan Wu,&nbsp;, and ,&nbsp;Xin Lu*,&nbsp;","doi":"10.1021/acsomega.5c03858","DOIUrl":"https://doi.org/10.1021/acsomega.5c03858","url":null,"abstract":"<p >While a few fullertubes satisfying the isolated pentagon rule have been experimentally synthesized, non-IPR isomers may become accessible through endohedral or exohedral functionalization. Density functional theory has been used to predict a novel class of non-IPR [3,3] fullertube chlorides, attributed to the release of strains from a triplet of directly fused pentagons (TDFP) in the fullertube end-caps. Additionally, we proposed that the growth of fullertubes proceeds via the continuous insertion of C₂ fragments, involving nonclassical fullerene intermediates containing heptagonal rings. These findings have significant implications for the synthesis of novel fullertube structures and, more broadly, carbon nanotubes.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"43698–43705"},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c03858","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Malonyl-Caffeoylquinic Acids and Malonyl-Flavonoid-Glucosides from Three Edible Apiaceae Plants Anthriscus Cerefolium, Anthriscus Sylvestris, and Chaerophyllum Bulbosum","authors":"Adila Nazli,&nbsp;, ,&nbsp;Mária Gáborová,&nbsp;, ,&nbsp;Tim Ausbüttel,&nbsp;, ,&nbsp;Bence Stipsicz,&nbsp;, ,&nbsp;Gergő Tóth,&nbsp;, ,&nbsp;Szilvia Bősze,&nbsp;, ,&nbsp;Szabolcs Béni*,&nbsp;, and ,&nbsp;Imre Boldizsár*,&nbsp;","doi":"10.1021/acsomega.5c03770","DOIUrl":"https://doi.org/10.1021/acsomega.5c03770","url":null,"abstract":"<p >Novel compounds, including four isomeric monomalonyl-dicaffeoylquinic acids (<b>4</b>–<b>7</b>), one dimalonyl-dicaffeoylquinic acid (<b>9</b>), and one flavonoid-dimalonyl-glucoside (<b>8</b>), along with three known flavonoid-monomalonyl-glucosides (<b>1</b>–<b>3</b>), were discovered in closely related edible Apiaceae plants: <i>Anthriscus cerefolium</i>, <i>Anthriscus sylvestris</i>, and <i>Chaerophyllum bulbosum</i>. Their structures were elucidated through comprehensive HPLC-UV-HR-MS/MS and NMR analyses, and isomeric malonyl-dicaffeoylquinic acids (<b>4</b>–<b>7</b>) were differentiated based on HPLC-MS/MS fragmentation characteristics. The study confirmed organ- and vegetation phase-specific accumulation, identifying optimal plant tissues for targeted isolation using a one-step preparative HPLC method. Malonyl-dicaffeoylquinic acids <b>4</b> and <b>9</b> exhibited significant cytotoxicity to nontumorous Vero E6 cells <i>in vitro</i> (IC₅₀ &lt; 10 μM). At the same time, the isolated compounds displayed structure-specific DPPH radical scavenging activity, underscoring their dual biological relevance.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"43656–43668"},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c03770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-Dimensional Numerical Simulation of 90Sr/90Y Separation by Countercurrent Electrophoresis to Produce Medical 90Y","authors":"Ziteng Gao,&nbsp;, ,&nbsp;Hu Zhang*,&nbsp;, ,&nbsp;Ting Yu,&nbsp;, ,&nbsp;Lu Qiao,&nbsp;, and ,&nbsp;Cunxiong Liu,&nbsp;","doi":"10.1021/acsomega.5c01958","DOIUrl":"https://doi.org/10.1021/acsomega.5c01958","url":null,"abstract":"<p >⁹⁰Y is used to label antibodies and treat the tumors. In a ⁹⁰Sr/⁹⁰Y generator, the decay of ⁹⁰Sr produces ⁹⁰Y. This study presented the development of a countercurrent electrophoretic separation device as a ⁹⁰Sr/⁹⁰Y generator for producing medical ⁹⁰Y. First, the complex stability constant was used to analyze the behavior of ethylenediaminetetraacetic acid (EDTA), citric acid (CIT), and ⁹⁰Sr/⁹⁰Y in different pH environments. Then, the concentration distribution in ⁹⁰Sr/⁹⁰Y separation via countercurrent electrophoresis was systematically investigated using COMSOL simulations, with specific focus on the effects of the temperature, applied voltage, and initial strontium concentration. Finally, the experimental validation further confirmed the technical feasibility of this separation method. As a result, the best simulation results indicated that the separation factor was 9.0 × 10⁸ at a temperature of 20 °C, a voltage of 1000 V, and a flow rate of 0.0001 m/s. After consideration of electro-osmotic flow, the separation factor is 9.8 × 10⁵, while the best experimental results showed that the separation factor was 8.7 × 10⁵ at 20 °C, 1000 V, and 0.0001 m/s.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"43499–43509"},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c01958","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidation of 5-HMF Catalyzed by N-Doped Carbon-Supported Non-Noble Metal Catalysts","authors":"Kaleeswari Kalimuthu,&nbsp;, ,&nbsp;Thinnaphat Poonsawat,&nbsp;, ,&nbsp;Peerapong Chumkaeo,&nbsp;, and ,&nbsp;Ekasith Somsook*,&nbsp;","doi":"10.1021/acsomega.5c06288","DOIUrl":"https://doi.org/10.1021/acsomega.5c06288","url":null,"abstract":"<p >2,5-Furandicarboxylic acid (FDCA) is an exceptionally promising biodegradable alternative to petroleum-derived terephthalic acid. The synthesis of FDCA from biomass-derived 5-hydroxymethylfurfural (HMF) has attracted significant attention. Herein, we report a straightforward method for synthesizing N-doped carbon-supported metal/metal phosphide catalysts developed using solid grinding techniques followed by pyrolysis. The synergistic effects of metal alloys and metal phosphides significantly influenced the product selectivity. The optimized catalyst (FeP-Co_0.2/NC) achieved a remarkable FDCA yield of 91.6% with complete HMF conversion at 150 °C for 24 h, using water as the solvent and O₂ as the oxidant. This study presents a sustainable and efficient approach for FDCA production. This discovery represents a sustainable method for producing FDCA with a high yield by employing environmentally friendly solvents and oxidizers.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"44415–44424"},"PeriodicalIF":4.3,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c06288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Enhancement of Caffeoylquinic Acid Derivative via UV Irradiation and Validation of Analytical Method in the Aerial Aster × chusanensis Y. S. Lim","authors":"Ju Yeon Kim,&nbsp;, ,&nbsp;Young-Hyun You,&nbsp;, ,&nbsp;Ji Eun Park,&nbsp;, ,&nbsp;Ha Yeon Byun,&nbsp;, ,&nbsp;Min-Ji Kang,&nbsp;, ,&nbsp;Han-Sol Sim,&nbsp;, ,&nbsp;Yun Gon Son,&nbsp;, ,&nbsp;Kwang Dong Kim,&nbsp;, ,&nbsp;Ki-Ho Son*,&nbsp;, and ,&nbsp;Jeong Yoon Kim*,&nbsp;","doi":"10.1021/acsomega.5c05804","DOIUrl":"https://doi.org/10.1021/acsomega.5c05804","url":null,"abstract":"<p ><i>Aster</i> × <i>chusanensis</i> Y.S.Lim is equipped with mass plant growth strategies that can potentially develop into functional foods. <i>A. chusanensis</i> was grown on a vertical farm until it was budding. The plants were transported to a growth chamber equipped with ultraviolet (UV)-A and UV-B lights and irradiated for 48 h. The base peak intensity (BPI) of the <i>A. chusanensis</i> control displayed eight predominant metabolites, namely, 3-O-caffeoylquinic acid, rutin, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, biorobin, luteolin-7-O-β-glucoside, 4,5-di-O-caffeoylquinic acid, and luteolin, as identified using LC-Q-TOF/MS analysis. UV-A-irradiated <i>A. chusanensis</i> showed an increase in the content of caffeoylquinic acid (CQA) derivatives (peaks 1, 3, 4, and 7). Thus, CQA-enhanced <i>A. chusanensis</i>, treated with UV-A irradiation, was used to develop analytical validation methods using HPLC-DAD. Quantitative analysis of the CQA derivatives was conducted based on the developed analytical method. The requirements for specificity, linearity, accuracy, and precision were met in accordance with the Korea Food and Drug Administration (KFDA) and the Association of Official Agricultural Chemists (AOAC) guidelines. The total contents of CQA derivatives in <i>A. chusanensis</i> were improved by ∼2.2 times (from 17,081 to 37,243 μg/g) following the UV-A irradiation treatment.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"44260–44269"},"PeriodicalIF":4.3,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c05804","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole-3-Butyric Acid (IBA) Derivatives for Root Architecture Modulation: Potent Promoters via In Vivo Conversion to IBA and Selective Inhibitors for Lateral Root Formation","authors":"Rie Kikuchi,&nbsp;, ,&nbsp;Takeshi Yamada,&nbsp;, ,&nbsp;Ami Watanabe,&nbsp;, ,&nbsp;Koyo Shibasaki,&nbsp;, ,&nbsp;Kazuki Arai,&nbsp;, ,&nbsp;Haruka Yamamoto,&nbsp;, ,&nbsp;Kouta Ibe,&nbsp;, and ,&nbsp;Sentaro Okamoto*,&nbsp;","doi":"10.1021/acsomega.5c07853","DOIUrl":"https://doi.org/10.1021/acsomega.5c07853","url":null,"abstract":"<p >Indole-3-butyric acid (IBA)-derived compounds, methyl 2-hydroxy-5-(1<i>H</i>-indole-3-yl)pentanoate (JAX-44) and its acid derivative (JAX-77), emerge as potent modulators of root architecture, exhibiting significant growth-promoting activity for lateral and adventitious roots. Crucially, unlike native IBA, which often inhibits primary root elongation at higher concentrations, JAX-44 and JAX-77 maintain primary root length while substantially increasing lateral root numbers, thereby optimizing the plant’s overall root system. Mass spectrometry analyses in <i>Arabidopsis thaliana</i> elucidated their mechanism: JAX-44 undergoes <i>in vivo</i> conversion to IBA via enzymatic hydrolysis to JAX-77, followed by oxidation to a keto-acid intermediate and finally YUCCA-mediated oxidative decarbonylation. This conversion process specifically requires an <i>N</i>-unsubstituted indole structure. Conversely, <i>N</i>- or <i>O</i>-methylation of JAX-44, yielding compounds JAX-86 and JAX-83, switches their activity from promotion to selective inhibition of lateral root formation. This inhibitory effect is attributed to the methylation preventing the necessary oxidative decarbonylation pathway. These results suggest that JAX-44 and JAX-77 are not only potentially superior plant growth regulators with enhanced flexibility and optimized root development for practical use but also valuable chemical biology tools that provide insight into auxin biology and the specific structural requirements for IBA bioactivity.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"44717–44727"},"PeriodicalIF":4.3,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c07853","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Regioisomeric Indole–Furanone Tubulin Inhibitors","authors":"Marcella Venettozzi,&nbsp;, ,&nbsp;Taylor E. Coburn,&nbsp;, ,&nbsp;Blake A. Evans,&nbsp;, ,&nbsp;Merrelle S. Grillo,&nbsp;, ,&nbsp;Aivy N. Le,&nbsp;, ,&nbsp;Alex M. Minayev,&nbsp;, ,&nbsp;Ameer H. Muse,&nbsp;, ,&nbsp;Joed G. Otchere,&nbsp;, ,&nbsp;Keira L. Potvin,&nbsp;, ,&nbsp;Aidan P. Staunton,&nbsp;, ,&nbsp;Charles M. Watroba,&nbsp;, ,&nbsp;Delaney M. Williams,&nbsp;, ,&nbsp;Kathryn E. Cole*,&nbsp;, ,&nbsp;Patricia Mowery*,&nbsp;, and ,&nbsp;Erin T. Pelkey*,&nbsp;","doi":"10.1021/acsomega.5c07360","DOIUrl":"https://doi.org/10.1021/acsomega.5c07360","url":null,"abstract":"<p >Tubulin is involved in microtubule function and affects mitosis, cell shape, migration, and the movement of organelles. Consequently, tubulin inhibitors have emerged as promising targets for cancer treatment. We previously identified a novel antitubulin motif that combines a furanone, indole, and electron-rich dimethoxyphenyl ring. The lead indole–furanone compound (<b>3</b>) demonstrated submicromolar potency on cancer cells and inhibited tubulin polymerization. To advance these findings, we synthesized a small library of analogs of <b>3</b>, analyzed their biological activities, and used molecular modeling to elucidate binding interactions in the tubulin colchicine binding site. To assess the impact on potency, we compared: (1) dimethoxy vs trimethoxy substitution of the phenyl A-ring, (2) <i>N</i>-indole substitution of the indole B-ring, and (3) regioisomers and anhydrides of the furanone C-ring. In the process of developing the synthesis of the furanone C-ring regioisomers, we identified that a modification of conditions (NaH/inert vs DBU/air) could be used to give either the corresponding furanones or maleic anhydrides. Of the 18 synthesized compounds, six are biologically active with two exhibiting submicromolar activity against HL-60 cells. Of the six active compounds, (1) three contained dimethoxyphenyl A-rings and three contained trimethoxyphenyl A-rings largely oriented toward the tubulin α-subunit, (2) the <i>N</i>-indole substitution appeared to be less impactful on activity although having the indole nitrogen pointing down into the colchicine binding site was favored, and (3) the furanone carbonyl group located <i>cis</i> to the di- or trimethoxyphenyl A-ring and pointing toward the α-subunit was favored.</p>","PeriodicalId":22,"journal":{"name":"ACS Omega","volume":"10 38","pages":"44675–44682"},"PeriodicalIF":4.3,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsomega.5c07360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}