New Multifunctional Platinum (IV) Complexes Incorporating Cannabidiol Active Moieties Elicit Mitochondrial Damage and Synergistically Boost Antitumor Efficacy

IF 3.7 2区化学 Q2 CHEMISTRY, APPLIED

Applied Organometallic Chemistry Pub Date : 2025-10-02 DOI:10.1002/aoc.70416

Rong Lv, Pengmin Shi, Jing Yang, Jian Zhao, Bo Yang, Chuanzhu Gao

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Abstract

This study focuses on the synthetic modification of satraplatin through axial position substitution by introducing the bioactive molecule cannabidiol (CBD) at the axial position, leading to novel multifunctional antitumor complexes S1–S5. The results demonstrate that the target complexes exhibit significantly optimized physicochemical properties with improved lipo–hydro partition coefficients, combining both lipophilic and hydrophilic characteristics that favor drug metabolism. Remarkably enhanced in vitro antitumor activity was observed: S3 showed 4.3-fold higher cytotoxicity than satraplatin in HCT-116 cells, with superior efficacy against drug-resistant cells. S5 demonstrated 22-fold greater antiproliferative activity than both parental satraplatin and CBD alone in A549 cells, likely attributable to its haloacetic axial group enhancing mitochondrial targeting for trifunctional synergistic antitumor effects. Mechanistic studies revealed that the complexes are reduced by ascorbic acid in vivo to release both CBD and Pt (II). CBD disrupts redox homeostasis through ROS accumulation and impairs mitochondrial membrane potential, synergizing with Pt (II)-induced DNA damage to promote cancer cell apoptosis. The introduction of bioactive moieties like CBD with excellent biological functions into the axial position of Pt (IV) complexes not only optimizes physicochemical properties but also enriches antitumor functionality. Compared with conventional platinum drugs, these complexes demonstrate significantly enhanced cytotoxicity (S3 is 9.5-fold more toxic than cisplatin in HCT-116 cells; S5 shows 33-fold higher antiproliferative activity in A549 cells) while maintaining superior activity against resistant cells through CBD-Pt (II) synergy. This study provides valuable insights for overcoming limitations of traditional platinum drugs and developing synergistic antitumor agents with enhanced efficacy.

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含大麻二酚活性基团的新型多功能铂（IV）配合物可诱导线粒体损伤并协同提高抗肿瘤疗效

本研究主要通过在轴向位置引入生物活性分子大麻二酚（cannabidiol， CBD），通过轴向位置取代对沙特铂进行合成修饰，得到新型多功能抗肿瘤复合物S1-S5。结果表明，目标配合物具有显著优化的物理化学性质，提高了脂-水分配系数，结合了亲脂和亲水的特性，有利于药物代谢。体外抗肿瘤活性显著增强：S3对HCT-116细胞的细胞毒性比沙特铂高4.3倍，对耐药细胞的疗效更优。在A549细胞中，S5的抗增殖活性比亲本沙特铂和单独的CBD高22倍，可能是由于其卤化乙酸轴向组增强了线粒体靶向三功能协同抗肿瘤作用。机制研究表明，体内抗坏血酸还原复合物释放CBD和Pt （II）。CBD通过ROS积累破坏氧化还原稳态，损害线粒体膜电位，与Pt （II）诱导的DNA损伤协同促进癌细胞凋亡。在Pt （IV）配合物的轴向位置引入CBD等具有优良生物学功能的生物活性基团，不仅优化了Pt （IV）配合物的理化性质，而且丰富了其抗肿瘤功能。与传统铂类药物相比，这些复合物显示出显著增强的细胞毒性（S3在HCT-116细胞中的毒性比顺铂高9.5倍；S5在A549细胞中的抗增殖活性比顺铂高33倍），同时通过CBD-Pt （II）协同作用保持对耐药细胞的优异活性。本研究为克服传统铂类药物的局限性，开发增效抗肿瘤药物提供了有价值的见解。

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来源期刊

Applied Organometallic Chemistry 化学-无机化学与核化学

CiteScore

7.80

自引率

10.30%

发文量

408

审稿时长

2.2 months

期刊介绍： All new compounds should be satisfactorily identified and proof of their structure given according to generally accepted standards. Structural reports, such as papers exclusively dealing with synthesis and characterization, analytical techniques, or X-ray diffraction studies of metal-organic or organometallic compounds will not be considered. The editors reserve the right to refuse without peer review any manuscript that does not comply with the aims and scope of the journal. Applied Organometallic Chemistry publishes Full Papers, Reviews, Mini Reviews and Communications of scientific research in all areas of organometallic and metal-organic chemistry involving main group metals, transition metals, lanthanides and actinides. All contributions should contain an explicit application of novel compounds, for instance in materials science, nano science, catalysis, chemical vapour deposition, metal-mediated organic synthesis, polymers, bio-organometallics, metallo-therapy, metallo-diagnostics and medicine. Reviews of books covering aspects of the fields of focus are also published.