{"title":"肿瘤微环境响应型Co(III)-Chrysin前药的开发:合成、激活分析和体外抗肿瘤评价。","authors":"Prakash Shukla, Krishna Kanta Choudhury, Kajol, Subhrata Behera, Janhabi Panigrahy, Rakesh Kumar Pathak","doi":"10.1002/cmdc.202500232","DOIUrl":null,"url":null,"abstract":"<p><p>Chrysin, a bioactive flavonoid with significant anticancer potential, is limited by its nonspecific toxicity and poor targetability. To overcome these challenges, we developed a cobalt(III)-chrysin prodrug (CCP) designed for selective activation in the hypoxic and reducing tumor microenvironment. The CCP was synthesized and characterized using spectroscopic and analytical techniques, demonstrating stability under physiological conditions and controlled release of chrysin in reducing environments, as confirmed by HPLC, LC-MS, and <sup>1</sup>H NMR studies. Biomolecular interaction studies demonstrated its binding to BSA and ctDNA. In vitro cytotoxicity assays in HeLa cells revealed that CCP effectively masked chrysin's activity, exhibiting an IC<sub>50</sub> value > 100 µM compared to free chrysin (IC<sub>50</sub> = 15 ± 2 µM). The activation of CCP with sodium ascorbate reduced its IC<sub>50</sub>, confirming its ability to release chrysin in a biologically relevant context. Live-dead assays validated the selective cytotoxicity of activated CCP, with increased cell death observed under reducing conditions. These findings highlight CCP as a promising prodrug system, combining the pharmacological benefits of chrysin with the advantages of metal-drug conjugates for hypoxia-activated cancer therapy.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500232"},"PeriodicalIF":3.4000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of a Tumor Microenvironment-Responsive Co(III)-Chrysin Prodrug: Synthesis, Activation Profiling, and In Vitro Antineoplastic Evaluation.\",\"authors\":\"Prakash Shukla, Krishna Kanta Choudhury, Kajol, Subhrata Behera, Janhabi Panigrahy, Rakesh Kumar Pathak\",\"doi\":\"10.1002/cmdc.202500232\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Chrysin, a bioactive flavonoid with significant anticancer potential, is limited by its nonspecific toxicity and poor targetability. To overcome these challenges, we developed a cobalt(III)-chrysin prodrug (CCP) designed for selective activation in the hypoxic and reducing tumor microenvironment. The CCP was synthesized and characterized using spectroscopic and analytical techniques, demonstrating stability under physiological conditions and controlled release of chrysin in reducing environments, as confirmed by HPLC, LC-MS, and <sup>1</sup>H NMR studies. Biomolecular interaction studies demonstrated its binding to BSA and ctDNA. In vitro cytotoxicity assays in HeLa cells revealed that CCP effectively masked chrysin's activity, exhibiting an IC<sub>50</sub> value > 100 µM compared to free chrysin (IC<sub>50</sub> = 15 ± 2 µM). The activation of CCP with sodium ascorbate reduced its IC<sub>50</sub>, confirming its ability to release chrysin in a biologically relevant context. Live-dead assays validated the selective cytotoxicity of activated CCP, with increased cell death observed under reducing conditions. These findings highlight CCP as a promising prodrug system, combining the pharmacological benefits of chrysin with the advantages of metal-drug conjugates for hypoxia-activated cancer therapy.</p>\",\"PeriodicalId\":147,\"journal\":{\"name\":\"ChemMedChem\",\"volume\":\" \",\"pages\":\"e202500232\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-08-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemMedChem\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/cmdc.202500232\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500232","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Development of a Tumor Microenvironment-Responsive Co(III)-Chrysin Prodrug: Synthesis, Activation Profiling, and In Vitro Antineoplastic Evaluation.
Chrysin, a bioactive flavonoid with significant anticancer potential, is limited by its nonspecific toxicity and poor targetability. To overcome these challenges, we developed a cobalt(III)-chrysin prodrug (CCP) designed for selective activation in the hypoxic and reducing tumor microenvironment. The CCP was synthesized and characterized using spectroscopic and analytical techniques, demonstrating stability under physiological conditions and controlled release of chrysin in reducing environments, as confirmed by HPLC, LC-MS, and 1H NMR studies. Biomolecular interaction studies demonstrated its binding to BSA and ctDNA. In vitro cytotoxicity assays in HeLa cells revealed that CCP effectively masked chrysin's activity, exhibiting an IC50 value > 100 µM compared to free chrysin (IC50 = 15 ± 2 µM). The activation of CCP with sodium ascorbate reduced its IC50, confirming its ability to release chrysin in a biologically relevant context. Live-dead assays validated the selective cytotoxicity of activated CCP, with increased cell death observed under reducing conditions. These findings highlight CCP as a promising prodrug system, combining the pharmacological benefits of chrysin with the advantages of metal-drug conjugates for hypoxia-activated cancer therapy.
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Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
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