Theranostic platforms have garnered considerable attention as a promising strategy to enhance the precision and efficacy of cancer treatment. Vicinal dithiol proteins (VDPs) are critical for maintaining cellular redox balance, and their dysregulation is associated with various pathological conditions, such as cancer, stroke and neurodegenerative diseases. Herein, we design a novel VDPs-activated theranostic prodrug, Lena-green, which incorporates an α, β-unsaturated acrylamide group as a recognition site for the first time. Upon exposure to VDPs, Lena-green conjugates the fluorophore to VDPs while releasing lenalidomide (Lena), a clinically established anticancer drug, enabling fluorescence-based tracking and achieving high drug release efficiency in vitro. In murine models of subcutaneous breast cancer, Lena-green exhibited significantly enhanced therapeutic efficacy. This innovative design provides a promising strategy for real-time monitoring of drug release, thereby improving the precision and effectiveness of cancer treatment.
{"title":"Vicinal dithiol proteins-triggered prodrug activation: A novel strategy for Cancer-specific imaging and therapy","authors":"Suntao Shi , Ruipeng Shen , Yating Chen, Mengzhao Zhang, Jingyi Liu, Chunlin Sun, Haijuan Zhang, Baoxin Zhang","doi":"10.1016/j.bioorg.2026.109552","DOIUrl":"10.1016/j.bioorg.2026.109552","url":null,"abstract":"<div><div>Theranostic platforms have garnered considerable attention as a promising strategy to enhance the precision and efficacy of cancer treatment. Vicinal dithiol proteins (VDPs) are critical for maintaining cellular redox balance, and their dysregulation is associated with various pathological conditions, such as cancer, stroke and neurodegenerative diseases. Herein, we design a novel VDPs-activated theranostic prodrug, <strong>Lena-green</strong>, which incorporates an α, β-unsaturated acrylamide group as a recognition site for the first time. Upon exposure to VDPs, <strong>Lena-green</strong> conjugates the fluorophore to VDPs while releasing lenalidomide (<strong>Lena</strong>), a clinically established anticancer drug, enabling fluorescence-based tracking and achieving high drug release efficiency in vitro. In murine models of subcutaneous breast cancer, <strong>Lena-green</strong> exhibited significantly enhanced therapeutic efficacy. This innovative design provides a promising strategy for real-time monitoring of drug release, thereby improving the precision and effectiveness of cancer treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109552"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.bioorg.2026.109550
Hailun Xia , Haoxin Fu , Lu Cao , Ruibin Li , Jun Wu , Peiqi Wang , Ren-ai Xu , Weihong Lin
Albendazole is a broad-spectrum antiparasitic benzimidazole and has potential for the treatment of tumors. The aim of this study was to investigate the potential inhibitory effects of 77 drugs on the metabolism of albendazole, and further to elaborate the inhibitory mechanism of apatinib on albendazole metabolism in vitro and in vivo, where the concentrations of albendazole and its metabolites were detected using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay. In vitro results showed that 10 drugs inhibited albendazole metabolism by more than 80%, with the half-maximal inhibitory concentrations (IC50) of apatinib in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 (rCYP3A4) being 0.47, 5.53 and 2.01 μM, respectively. Moreover, the inhibition of albendazole by apatinib was non-time-dependent. In addition, the inhibitory mechanisms were mixed consisting of non-competitive and un-competitive for RLM, and competitive and non-competitive for HLM and rCYP3A4. Pharmacokinetic parameters in Sprague-Dawley rats showed that apatinib caused significant increases in AUC(0-t), AUC(0-∞), Cmax, Tmax and t1/2, while a significant decrease in CLz/F for albendazole. For the metabolites albendazole sulfoxide and hydroxyalbendazole, apatinib caused significant increases in AUC(0-t), AUC(0-∞), and Tmax, while a significant decrease in CLz/F. In summary, apatinib could inhibit the metabolism of albendazole in vitro and in vivo, so albendazole should be closely monitored for adverse effects when used in combination with apatinib and discontinued if necessary.
{"title":"Effect of apatinib on albendazole metabolism in vitro and in vivo","authors":"Hailun Xia , Haoxin Fu , Lu Cao , Ruibin Li , Jun Wu , Peiqi Wang , Ren-ai Xu , Weihong Lin","doi":"10.1016/j.bioorg.2026.109550","DOIUrl":"10.1016/j.bioorg.2026.109550","url":null,"abstract":"<div><div>Albendazole is a broad-spectrum antiparasitic benzimidazole and has potential for the treatment of tumors. The aim of this study was to investigate the potential inhibitory effects of 77 drugs on the metabolism of albendazole, and further to elaborate the inhibitory mechanism of apatinib on albendazole metabolism <em>in vitro</em> and <em>in vivo</em>, where the concentrations of albendazole and its metabolites were detected using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay. <em>In vitro</em> results showed that 10 drugs inhibited albendazole metabolism by more than 80%, with the half-maximal inhibitory concentrations (IC<sub>50</sub>) of apatinib in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 (rCYP3A4) being 0.47, 5.53 and 2.01 μM, respectively. Moreover, the inhibition of albendazole by apatinib was non-time-dependent. In addition, the inhibitory mechanisms were mixed consisting of non-competitive and un-competitive for RLM, and competitive and non-competitive for HLM and rCYP3A4. Pharmacokinetic parameters in Sprague-Dawley rats showed that apatinib caused significant increases in AUC<sub>(0-t)</sub>, AUC<sub>(0-∞)</sub>, C<sub>max</sub>, T<sub>max</sub> and t<sub>1/2</sub>, while a significant decrease in CL<sub>z/F</sub> for albendazole. For the metabolites albendazole sulfoxide and hydroxyalbendazole, apatinib caused significant increases in AUC<sub>(0-t)</sub>, AUC<sub>(0-∞)</sub>, and T<sub>max</sub>, while a significant decrease in CL<sub>z/F</sub>. In summary, apatinib could inhibit the metabolism of albendazole <em>in vitro</em> and <em>in vivo</em>, so albendazole should be closely monitored for adverse effects when used in combination with apatinib and discontinued if necessary.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109550"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.bioorg.2026.109533
Zhuo Xi , Jin Wang , Xiaoxue Ge , Hongyan Zhang , Yawen Ma
KAT6 A (lysine acetyltransferase 6 A) is a member of the MYST family of histone acetyltransferases (HATs) that plays a pivotal role in regulating gene expression through the acetylation of histones and non-histone proteins. Dysregulation of KAT6A has been implicated in various cancers, making it an attractive target for therapeutic intervention. Over the past, significant advancements have been made in the development of small-molecule KAT6A inhibitors. PF-07248144 has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer models and is currently undergoing clinical evaluation. The development of these inhibitors has been facilitated by structure-based drug design and high-throughput screening, enhancing their selectivity and pharmacokinetic properties. This review provides a comprehensive overview of the structural and biological functions of KAT6A, its role in tumor progression, and the therapeutic potential of its inhibition. It summarizes the advancements in KAT6A inhibitor development from 2019 to the present, emphasizing the optimization processes from lead compounds to clinical candidates.
KAT6 A （lysine acetyltransferase 6a）是MYST组蛋白乙酰转移酶（histone acetyltransferases, HATs）家族的一员，通过组蛋白和非组蛋白的乙酰化，在调节基因表达中起关键作用。KAT6A的失调与多种癌症有关，使其成为治疗干预的一个有吸引力的靶点。过去，在开发小分子KAT6A抑制剂方面取得了重大进展。PF-07248144在雌激素受体阳性（ER+）乳腺癌模型中显示出抗肿瘤活性，目前正在进行临床评估。基于结构的药物设计和高通量筛选促进了这些抑制剂的开发，增强了它们的选择性和药代动力学性质。本文综述了KAT6A的结构和生物学功能、其在肿瘤进展中的作用以及抑制KAT6A的治疗潜力。总结了2019年至今KAT6A抑制剂的开发进展，重点介绍了从先导化合物到临床候选药物的优化过程。
{"title":"Dancing with KAT6A: Current advances and therapeutic potential in oncology of KAT6A inhibitors","authors":"Zhuo Xi , Jin Wang , Xiaoxue Ge , Hongyan Zhang , Yawen Ma","doi":"10.1016/j.bioorg.2026.109533","DOIUrl":"10.1016/j.bioorg.2026.109533","url":null,"abstract":"<div><div>KAT6 A (lysine acetyltransferase 6 A) is a member of the MYST family of histone acetyltransferases (HATs) that plays a pivotal role in regulating gene expression through the acetylation of histones and non-histone proteins. Dysregulation of KAT6A has been implicated in various cancers, making it an attractive target for therapeutic intervention. Over the past, significant advancements have been made in the development of small-molecule KAT6A inhibitors. PF-07248144 has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer models and is currently undergoing clinical evaluation. The development of these inhibitors has been facilitated by structure-based drug design and high-throughput screening, enhancing their selectivity and pharmacokinetic properties. This review provides a comprehensive overview of the structural and biological functions of KAT6A, its role in tumor progression, and the therapeutic potential of its inhibition. It summarizes the advancements in KAT6A inhibitor development from 2019 to the present, emphasizing the optimization processes from lead compounds to clinical candidates.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109533"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.bioorg.2026.109536
Boao Li , Liang Jiao , Yueyan Zhang
Although immunotherapy has reshaped the treatment landscape for gastrointestinal (GI) malignancies, durable clinical benefit is achieved in only a subset of patients, largely due to the emergence of immune resistance. Accumulating evidence highlights histone lactylation, an epigenetic modification driven by excessive lactate accumulation, as a pivotal mediator linking tumor metabolism to immune suppression. By reprogramming transcriptional networks within the tumor microenvironment, histone lactylation skews macrophages toward an immunosuppressive phenotype and compromises T-cell effector function, thereby facilitating tumor immune escape. In metabolically active GI tumors with pronounced lactate production, aberrant histone lactylation contributes to the establishment of a profoundly immunosuppressive niche that undermines responses to immune checkpoint inhibitors. Targeting lactylation-related pathways has therefore gained attention as a novel therapeutic avenue, with the potential to restore antitumor immune activity, enhance cytotoxic lymphocyte function, and sensitize tumors to immunotherapy. This article summarizes current understanding of the crosstalk between lactate metabolism, histone lactylation, and immune regulation, and highlights therapeutic approaches targeting this epigenetic axis to enhance immunotherapy efficacy in GI cancers.
{"title":"Pharmacological inhibition of histone Lactylation enhances immunotherapy efficacy in gastrointestinal cancers","authors":"Boao Li , Liang Jiao , Yueyan Zhang","doi":"10.1016/j.bioorg.2026.109536","DOIUrl":"10.1016/j.bioorg.2026.109536","url":null,"abstract":"<div><div>Although immunotherapy has reshaped the treatment landscape for gastrointestinal (GI) malignancies, durable clinical benefit is achieved in only a subset of patients, largely due to the emergence of immune resistance. Accumulating evidence highlights histone lactylation, an epigenetic modification driven by excessive lactate accumulation, as a pivotal mediator linking tumor metabolism to immune suppression. By reprogramming transcriptional networks within the tumor microenvironment, histone lactylation skews macrophages toward an immunosuppressive phenotype and compromises T-cell effector function, thereby facilitating tumor immune escape. In metabolically active GI tumors with pronounced lactate production, aberrant histone lactylation contributes to the establishment of a profoundly immunosuppressive niche that undermines responses to immune checkpoint inhibitors. Targeting lactylation-related pathways has therefore gained attention as a novel therapeutic avenue, with the potential to restore antitumor immune activity, enhance cytotoxic lymphocyte function, and sensitize tumors to immunotherapy. This article summarizes current understanding of the crosstalk between lactate metabolism, histone lactylation, and immune regulation, and highlights therapeutic approaches targeting this epigenetic axis to enhance immunotherapy efficacy in GI cancers.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109536"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.bioorg.2026.109534
Hong-ye Liu , Ying-hao Sun , Yan-ping Wang , Xu Zhang , Shuai Guo , Lin Wang , Fan-hao Meng , Ting-jian Zhang
Tropomyosin receptor kinase (TRK), belonging to the tyrosine kinase family, is associated with tumor proliferation, invasion, and survival in various cancers. Upon activation by neurotrophic factors, TRK regulates crucial cellular processes through downstream signaling pathways. Dysregulation of TRK signaling can lead to a range of diseases including cancers. Moreover, mutations in TRK kinases leading to resistance remain a critical issue, necessitating the discovery of new TRK inhibitors to overcome acquired resistance. Recently, several selective TRK inhibitors have been reported, making it possible to address off-target effects and adverse reactions associated with the target. This review summarizes the recent advances in small molecular TRK inhibitors with diverse structural types, activities, and selectivity. It highlights promising small molecules that have shown breakthrough achievements in the field.
{"title":"TRK inhibitors in cancer therapeutics: Recent advances and future perspectives","authors":"Hong-ye Liu , Ying-hao Sun , Yan-ping Wang , Xu Zhang , Shuai Guo , Lin Wang , Fan-hao Meng , Ting-jian Zhang","doi":"10.1016/j.bioorg.2026.109534","DOIUrl":"10.1016/j.bioorg.2026.109534","url":null,"abstract":"<div><div>Tropomyosin receptor kinase (TRK), belonging to the tyrosine kinase family, is associated with tumor proliferation, invasion, and survival in various cancers. Upon activation by neurotrophic factors, TRK regulates crucial cellular processes through downstream signaling pathways. Dysregulation of TRK signaling can lead to a range of diseases including cancers. Moreover, mutations in TRK kinases leading to resistance remain a critical issue, necessitating the discovery of new TRK inhibitors to overcome acquired resistance. Recently, several selective TRK inhibitors have been reported, making it possible to address off-target effects and adverse reactions associated with the target. This review summarizes the recent advances in small molecular TRK inhibitors with diverse structural types, activities, and selectivity. It highlights promising small molecules that have shown breakthrough achievements in the field.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109534"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Two novel alkaloids, pegaharmolinones A and B (1–2), featuring an unprecedented 6/6/5/5 tetracyclic skeleton based on a 1,4-dihydro-6H-pyrrolo[2′,3′:3,4]pyrrolo[2,1-b]quinazolin-6-one core, and nineteen undescribed alkaloids, including luotonins G–L (3–7, 11) and pegaharmnolines A–K (18–22, 26, 29–30, 33–35), as well as fourteen known analogs, were isolated from the aerial parts of Peganum harmala. Their structures and absolute configurations were determined through analysis of NMR, HR-ESI-MS spectroscopic data, and ECD calculations, supported by a strategy of CASE-DFT. A plausible biosynthetic pathway for 1 and 2 was proposed. The anticancer activity in vitro was evaluated using the CCK-8 method, revealing that compound 22 exhibited potent efficacy and high selectivity, with an IC50 value of 6.49 μM and a selectivity index greater than 10. A series of bioassay suggested that 22 significantly suppressed the proliferation and migration of Hep G2 cells, and induced mitochondria-mediated apoptosis through both intrinsic and extrinsic pathways. Moreover, the SAR analysis of the tested active compounds provides structural modification strategies for the natural lead candidates 2 and 22.
{"title":"Identification of quinazolinone and quinoline alkaloids from Peganum harmala L. inducing mitochondria-mediated apoptosis in liver cancer","authors":"Qin Zhang, Jin-Zheng Yu, Chun-Lei Yuan, Fan-Zhu Meng, Meng-Yue Yang, Han-Gao Yang, Fang-Shen Liu, Sheng-Ge Li, Ying Zhang, Yi-Yang Liu, Yan-Hui Zan, Da-Hong Li, Hui-Ming Hua","doi":"10.1016/j.bioorg.2026.109528","DOIUrl":"10.1016/j.bioorg.2026.109528","url":null,"abstract":"<div><div>Two novel alkaloids, pegaharmolinones A and B (<strong>1–2</strong>), featuring an unprecedented 6/6/5/5 tetracyclic skeleton based on a 1,4-dihydro-6<em>H</em>-pyrrolo[2′,3′:3,4]pyrrolo[2,1-<em>b</em>]quinazolin-6-one core, and nineteen undescribed alkaloids, including luotonins G–L (<strong>3–7</strong>, <strong>11</strong>) and pegaharmnolines A–K (<strong>18–22</strong>, <strong>26</strong>, <strong>29–30</strong>, <strong>33–35</strong>), as well as fourteen known analogs, were isolated from the aerial parts of <em>Peganum harmala</em>. Their structures and absolute configurations were determined through analysis of NMR, HR-ESI-MS spectroscopic data, and ECD calculations, supported by a strategy of CASE-DFT. A plausible biosynthetic pathway for <strong>1</strong> and <strong>2</strong> was proposed. The anticancer activity in vitro was evaluated using the CCK-8 method, revealing that compound <strong>22</strong> exhibited potent efficacy and high selectivity, with an IC<sub>50</sub> value of 6.49 μM and a selectivity index greater than 10. A series of bioassay suggested that <strong>22</strong> significantly suppressed the proliferation and migration of Hep G2 cells, and induced mitochondria-mediated apoptosis through both intrinsic and extrinsic pathways. Moreover, the SAR analysis of the tested active compounds provides structural modification strategies for the natural lead candidates <strong>2</strong> and <strong>22</strong>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109528"},"PeriodicalIF":4.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109527
Yuxiao Xia , Jianpeng Cao , Dongkun Xu , Xue Jiang , Qian Liu , Lina Liu , Wenling Tu , Ying Huang , Quanyu Zhou , Yuhong Shi , Hua Pang
Objective
Prolonging the systemic half-life of fibroblast-activation-protein inhibitors (FAPIs) through an albumin-binding module is an attractive strategy to amplify intratumoral dose delivery. We report a head-to-head comparison of the identical scaffold FAPI-X5 labeled with 68Ga, 177Lu and the emerging 47Sc.
Methods
FAPI-X5 was designed by in-silico docking, synthesized, and radiolabeled with 68Ga, 177Lu or 47Sc. Radiochemical purity, stability, lipophilicity, albumin binding, cellular uptake, biodistribution, micro-PET/SPECT imaging and single-dose radiotherapy (18.5–55.5 MBq) were evaluated in U87MG-FAP tumor-bearing mice.
Results
All conjugates showed >95% radiochemical purity and > 40% albumin binding. 68Ga-FAPI-X5 achieved rapid tumor uptake (23.6%ID/g at 2 h) and a tumor-to-liver SUVmean ratio of 1.3, enabling high-contrast PET imaging. 177Lu- and 47Sc-FAPI-X5 exhibited prolonged tumor retention but prominent hepatic accumulation (34%ID/g for 47Sc at 2 h), yielding tumor-to-liver SUVmean ≤0.28 and simplified hepatic absorbed doses >30 Gy. 47Sc-FAPI-X5 additionally displayed elevated bone uptake (17%ID/g) and marrow doses 35–60% higher than the 177Lu analogue. Therapy studies showed only cytostatic effects (T/C 36–43%) accompanied by dose-dependent hepatogastrointestinal toxicity.
Conclusion
While 68Ga-FAPI-X5 is a promising PET tracer, the unfavorable tumor-to-liver and tumor-to-bone ratios of 47Sc-FAPI-X5 preclude its clinical translation. Future 47Sc-FAPI development must prioritize scandium-optimized chelators and nephrophilic scaffold redesign.
{"title":"Comparative study of 47Sc and 177Lu-labeled albumin binder-conjugated FAPI radiopharmaceuticals","authors":"Yuxiao Xia , Jianpeng Cao , Dongkun Xu , Xue Jiang , Qian Liu , Lina Liu , Wenling Tu , Ying Huang , Quanyu Zhou , Yuhong Shi , Hua Pang","doi":"10.1016/j.bioorg.2026.109527","DOIUrl":"10.1016/j.bioorg.2026.109527","url":null,"abstract":"<div><h3>Objective</h3><div>Prolonging the systemic half-life of fibroblast-activation-protein inhibitors (FAPIs) through an albumin-binding module is an attractive strategy to amplify intratumoral dose delivery. We report a head-to-head comparison of the identical scaffold FAPI-X5 labeled with <sup>68</sup>Ga, <sup>177</sup>Lu and the emerging <sup>47</sup>Sc.</div></div><div><h3>Methods</h3><div>FAPI-X5 was designed by in-silico docking, synthesized, and radiolabeled with <sup>68</sup>Ga, <sup>177</sup>Lu or <sup>47</sup>Sc. Radiochemical purity, stability, lipophilicity, albumin binding, cellular uptake, biodistribution, micro-PET/SPECT imaging and single-dose radiotherapy (18.5–55.5 MBq) were evaluated in U87MG-FAP tumor-bearing mice.</div></div><div><h3>Results</h3><div>All conjugates showed >95% radiochemical purity and > 40% albumin binding. <sup>68</sup>Ga-FAPI-X5 achieved rapid tumor uptake (23.6%ID/g at 2 h) and a tumor-to-liver SUVmean ratio of 1.3, enabling high-contrast PET imaging. <sup>177</sup>Lu- and <sup>47</sup>Sc-FAPI-X5 exhibited prolonged tumor retention but prominent hepatic accumulation (34%ID/g for <sup>47</sup>Sc at 2 h), yielding tumor-to-liver SUVmean ≤0.28 and simplified hepatic absorbed doses >30 Gy. <sup>47</sup>Sc-FAPI-X5 additionally displayed elevated bone uptake (17%ID/g) and marrow doses 35–60% higher than the <sup>177</sup>Lu analogue. Therapy studies showed only cytostatic effects (T/C 36–43%) accompanied by dose-dependent hepatogastrointestinal toxicity.</div></div><div><h3>Conclusion</h3><div>While <sup>68</sup>Ga-FAPI-X5 is a promising PET tracer, the unfavorable tumor-to-liver and tumor-to-bone ratios of <sup>47</sup>Sc-FAPI-X5 preclude its clinical translation. Future <sup>47</sup>Sc-FAPI development must prioritize scandium-optimized chelators and nephrophilic scaffold redesign.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109527"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The development of new antitubercular drugs is critically hindered by the persistent and adaptive nature of Mycobacterium tuberculosis (Mtb), underscoring an urgent need for innovative therapeutic strategies. In this work, a series of structurally varied 2-aminothiophene and 2-aminothiazole derivatives was designed, synthesized, and characterized using FT-IR, NMR, HRMS, and single-crystal X-ray techniques. The thiophene analogues were prepared via the Gewald reaction, while thiazole derivatives were obtained through Hantzsch synthesis, with structural diversity achieved by modifying alkyl, ester, and fused ring groups. Several compounds exhibited potent antitubercular activity against Mtb H37Rv, with 4h, 4k, and 4l showing MIC values of 0.78 μg/mL, comparable to the standard drug Ethambutol. SAR studies revealed that linear alkyl chains enhanced activity, whereas aryl and fused rings were less favourable. Additionally, compounds 4q, 4s, 7g, 7o, and 9e emerged as moderate antibacterial leads against both Gram-positive and Gram-negative bacteria. Cytotoxicity assays for the potent compounds were performed in Vero cells and THP-1 cells, supporting a favourable safety profile and selective activity against Mtb. Furthermore, target prediction, molecular docking, along with DFT and ADMET analyses, provided valuable insights into their putative molecular targets, binding modes, and the drug-like and electronic properties that influence bioactivity. Collectively, these results identify compound 4k as a promising lead candidate against Mtb, underscoring the potential of the 2-aminothiophene scaffold as a valuable framework for antitubercular drug discovery. These findings encourage further exploration of 2-aminothiophene and 2-aminothiazole scaffolds by medicinal chemists for the development of novel, potent, and selective antitubercular and antibacterial drug candidates.
{"title":"2-Aminothiophene and 2-aminothiazole scaffolds as potent antimicrobial agents: Design, synthesis, biological evaluation, and computational insights","authors":"Munugala Chandrakanth , Jyothi Kumari , Paramita Pakhira , Dharmarajan Sriram , Siddhardha Busi , Sampathkumar Ranganathan , Chandni Kumari , Sonam Bisla , Mukesh Pasupuleti , Ramesh Gondru , Jesu Arockiaraj , Janardhan Banothu","doi":"10.1016/j.bioorg.2026.109511","DOIUrl":"10.1016/j.bioorg.2026.109511","url":null,"abstract":"<div><div>The development of new antitubercular drugs is critically hindered by the persistent and adaptive nature of <em>Mycobacterium tuberculosis (Mtb)</em>, underscoring an urgent need for innovative therapeutic strategies. In this work, a series of structurally varied 2-aminothiophene and 2-aminothiazole derivatives was designed, synthesized, and characterized using FT-IR, NMR, HRMS, and single-crystal X-ray techniques. The thiophene analogues were prepared <em>via</em> the Gewald reaction, while thiazole derivatives were obtained through Hantzsch synthesis, with structural diversity achieved by modifying alkyl, ester, and fused ring groups. Several compounds exhibited potent antitubercular activity against <em>Mtb H37Rv</em>, with <strong>4</strong><strong>h</strong>, <strong>4</strong><strong>k</strong>, and <strong>4</strong><strong>l</strong> showing MIC values of 0.78 μg/mL, comparable to the standard drug Ethambutol. SAR studies revealed that linear alkyl chains enhanced activity, whereas aryl and fused rings were less favourable. Additionally, compounds <strong>4q</strong>, <strong>4</strong><strong>s</strong>, <strong>7</strong><strong>g, 7o</strong>, and <strong>9e</strong> emerged as moderate antibacterial leads against both Gram-positive and Gram-negative bacteria. Cytotoxicity assays for the potent compounds were performed in Vero cells and THP-1 cells, supporting a favourable safety profile and selective activity against <em>Mtb</em>. Furthermore, target prediction, molecular docking, along with DFT and ADMET analyses, provided valuable insights into their putative molecular targets, binding modes, and the drug-like and electronic properties that influence bioactivity. Collectively, these results identify compound <strong>4</strong><strong>k</strong> as a promising lead candidate against <em>Mtb</em>, underscoring the potential of the 2-aminothiophene scaffold as a valuable framework for antitubercular drug discovery. These findings encourage further exploration of 2-aminothiophene and 2-aminothiazole scaffolds by medicinal chemists for the development of novel, potent, and selective antitubercular and antibacterial drug candidates.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109511"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109525
Xinmo Gui , Jie Wang , Xian Wang , Min Xie , Guangyuan Yin , Liangkai Shao , Liqing Zheng , Peixin Han , Jiong Zhang
Carbonic anhydrase represents a highly promising target in drug discovery, as the dysregulation or overexpression of its various isoforms in humans is closely associated with a range of diseases. Carbonic anhydrase inhibitors can modulate the activity of human carbonic anhydrases, thereby exerting diuretic, anti-glaucoma, antiepileptic, analgesic, antitumor, and anti-obesity effects. In this study, to obtain structurally diverse human carbonic anhydrase inhibitors, we employed a modular click chemistry library strategy to construct 401 para-aryl sulfonamide-triazoles in 96-well plates. Through this diversity-oriented clicking approach followed by enzymatic activity screening, we identified 16 hit compounds that exhibit potent inhibitory activity against hCA II with considerable structural diversity. Among them, compounds 3o and 3h showed excellent inhibitory activity against hCA II, with Ki values of 1.65 nM and 2.26 nM, respectively, while compounds such as 3e also demonstrated certain selectivity among different hCA isoforms. Furthermore, these compounds displayed favorable predicted drug-like properties.
{"title":"Diversity-oriented synthesis of Para-aryl Sulfonamides as potent human carbonic anhydrase inhibitors via modular click chemistry","authors":"Xinmo Gui , Jie Wang , Xian Wang , Min Xie , Guangyuan Yin , Liangkai Shao , Liqing Zheng , Peixin Han , Jiong Zhang","doi":"10.1016/j.bioorg.2026.109525","DOIUrl":"10.1016/j.bioorg.2026.109525","url":null,"abstract":"<div><div>Carbonic anhydrase represents a highly promising target in drug discovery, as the dysregulation or overexpression of its various isoforms in humans is closely associated with a range of diseases. Carbonic anhydrase inhibitors can modulate the activity of human carbonic anhydrases, thereby exerting diuretic, anti-glaucoma, antiepileptic, analgesic, antitumor, and anti-obesity effects. In this study, to obtain structurally diverse human carbonic anhydrase inhibitors, we employed a modular click chemistry library strategy to construct 401 <em>para</em>-aryl sulfonamide-triazoles in 96-well plates. Through this diversity-oriented clicking approach followed by enzymatic activity screening, we identified 16 hit compounds that exhibit potent inhibitory activity against hCA II with considerable structural diversity. Among them, compounds <strong>3o</strong> and <strong>3h</strong> showed excellent inhibitory activity against hCA II, with K<sub>i</sub> values of 1.65 nM and 2.26 nM, respectively, while compounds such as <strong>3e</strong> also demonstrated certain selectivity among different hCA isoforms. Furthermore, these compounds displayed favorable predicted drug-like properties.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109525"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109494
Ghada M. Sadiq , Mohamed A. Mawhoup , Mai M.M. Tawfik , Mahmoud Mostafa , Amany Abdelaziz , Ramadan Yahia , Rehab Mahmoud Abd El-Baky , Mohamed Abdel-Aziz , Gamal El-Din A. Abuo-Rahma , Aliaa M. Mohassab
A series of novel phenylpiperazine-based carbodithioate derivatives (3a–j) were designed, synthesized, formulated as PEG-Niosomes and evaluated for their potential hydrogen sulphide (H2S) donating properties and their antifungal activities. Structural modifications were inspired by the antifungal drug tolnaftate, incorporating a dithiocarbamate moiety to enhance biological activity and target engagement. H2S-releasing capacity was quantified via the methylene blue assay. Compound 3j (S-phenacyl p-chloro derivative) exhibiting the highest release (89.71%), followed by compounds 3a and 3i. Antifungal efficacy against Candida albicans was determined using the microbroth dilution method, where compounds 3a, 3b, 3f, 3i and 3j demonstrated potent inhibitory activity (MIC = 4.68 μg/mL), exceeding that of fluconazole. Further investigations revealed that these compounds also effectively suppressed hyphal formation and biofilm development, two major virulence factors of C. albicans. Notably, compound 3j exhibited superior performance across all assays. In a preliminary safety evaluation, compound 3j displayed low cytotoxicity toward mammalian fibroblasts (WS-1) (IC₅₀ = 65.73 ± 4.20 μg/mL) compared to doxorubicin (IC₅₀ = 26.72 ± 2.20 μg/mL), providing an 14-fold selectivity index relative to its antifungal MIC (4.68 μg/mL). Molecular docking studies corroborated these findings by showing favorable binding of compound 3j to the lanosterol 14α-demethylase enzyme (CYP51), highlighting π–sulfur and hydrophobic interactions critical for binding affinity. Additionally, compound 3j directly inhibited CYP51 in vitro (IC₅₀ = 0.331 ± 0.025 μM), showing stronger inhibition than the reference azole fluconazole (IC₅₀ = 1.388 ± 0.099 μM. H₂S release was also verified by scavenger reversal. In the presence of MgO (1.5 mg/mL), the antifungal activity of compound 3j decreased, with the MIC rising to 32 μg/mL. These results underscore the potential of phenylpiperazine dithioates, particularly compound 3j, as promising antifungal agent with multi-target activity. Additionally, the PEG-Niosomes of compound 3j represent a promising delivery system for enhancing the dissolution and potential bioavailability of compound 3j.
{"title":"Phenylpiperazine/dithioates as novel H2S donors: design, synthesis, H2S release, formulation as PEG-niosomes and antifungal activity against Candida albicans","authors":"Ghada M. Sadiq , Mohamed A. Mawhoup , Mai M.M. Tawfik , Mahmoud Mostafa , Amany Abdelaziz , Ramadan Yahia , Rehab Mahmoud Abd El-Baky , Mohamed Abdel-Aziz , Gamal El-Din A. Abuo-Rahma , Aliaa M. Mohassab","doi":"10.1016/j.bioorg.2026.109494","DOIUrl":"10.1016/j.bioorg.2026.109494","url":null,"abstract":"<div><div>A series of novel phenylpiperazine-based carbodithioate derivatives <strong>(3a–j)</strong> were designed, synthesized, formulated as PEG-Niosomes and evaluated for their potential hydrogen sulphide (H<sub>2</sub>S) donating properties and their antifungal activities. Structural modifications were inspired by the antifungal drug tolnaftate, incorporating a dithiocarbamate moiety to enhance biological activity and target engagement. H<sub>2</sub>S-releasing capacity was quantified <em>via</em> the methylene blue assay. Compound <strong>3j</strong> (S-phenacyl p-chloro derivative) exhibiting the highest release (89.71%), followed by compounds <strong>3a</strong> and <strong>3i</strong>. Antifungal efficacy against <em>Candida albicans</em> was determined using the microbroth dilution method, where compounds <strong>3a, 3b, 3f, 3i</strong> and <strong>3j</strong> demonstrated potent inhibitory activity (MIC = 4.68 μg/mL), exceeding that of fluconazole. Further investigations revealed that these compounds also effectively suppressed hyphal formation and biofilm development, two major virulence factors of <em>C. albicans</em>. Notably, compound <strong>3j</strong> exhibited superior performance across all assays. In a preliminary safety evaluation, compound <strong>3j</strong> displayed low cytotoxicity toward mammalian fibroblasts (WS-1) (IC₅₀ = 65.73 ± 4.20 μg/mL) compared to doxorubicin (IC₅₀ = 26.72 ± 2.20 μg/mL), providing an 14-fold selectivity index relative to its antifungal MIC (4.68 μg/mL). Molecular docking studies corroborated these findings by showing favorable binding of compound <strong>3j</strong> to the lanosterol 14α-demethylase enzyme (CYP51), highlighting π–sulfur and hydrophobic interactions critical for binding affinity. Additionally, compound <strong>3j</strong> directly inhibited CYP51 <em>in vitro</em> (IC₅₀ = 0.331 ± 0.025 μM), showing stronger inhibition than the reference azole fluconazole (IC₅₀ = 1.388 ± 0.099 μM. H₂S release was also verified by scavenger reversal. In the presence of MgO (1.5 mg/mL), the antifungal activity of compound <strong>3j</strong> decreased, with the MIC rising to 32 μg/mL. These results underscore the potential of phenylpiperazine dithioates, particularly compound <strong>3j</strong>, as promising antifungal agent with multi-target activity. Additionally, the PEG-Niosomes of compound <strong>3j</strong> represent a promising delivery system for enhancing the dissolution and potential bioavailability of compound <strong>3j</strong>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109494"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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