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。

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-20 DOI:10.1002/cmdc.202500232
Prakash Shukla, Krishna Kanta Choudhury, Kajol, Subhrata Behera, Janhabi Panigrahy, Rakesh Kumar Pathak
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引用次数: 0

摘要

菊花素是一种具有重要抗癌潜力的生物活性类黄酮,但其非特异性毒性和靶向性较差。为了克服这些挑战,我们开发了一种钴(III)-chrysin前药(CCP),设计用于在缺氧和减少肿瘤微环境中选择性激活。通过HPLC、LC-MS和1H NMR研究证实,CCP在生理条件下具有稳定性,并在还原环境中具有控制释放的特性。生物分子相互作用研究表明其与BSA和ctDNA结合。体外对HeLa细胞的细胞毒性实验表明,CCP有效地掩盖了菊花素的活性,与游离菊花素相比,其IC50值为100µM (IC50 = 15±2µM)。抗坏血酸钠激活CCP降低了其IC50,证实了其在生物学相关背景下释放菊花素的能力。活死实验证实了活化CCP的选择性细胞毒性,在还原条件下观察到细胞死亡增加。这些发现强调CCP作为一个有前途的前药系统,结合了菊花素的药理作用和金属-药物偶联物的优势,用于缺氧激活的癌症治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: 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. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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