The anti-neoplastic potency of epoxy-substituted polyaromatic platinum(II) and platinum(IV) complexes against A549 lung cancer cells

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-05-08 DOI:10.1016/j.ejmech.2025.117734

Rouba Al Sayegh , Aleen Khoury , Maria George Elias , Najwa Mansour , Stephanie Mehanna , Amjad Slika , Costantine F. Daher , Janice R. Aldrich-Wright , Robin I. Taleb

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Abstract

A novel platinum(II) complex, Pt^II56OSS, coordinated to 5,6-epoxy-5,6-dihydro-1,10-phenanthroline and its platinum(IV) di-hydroxido derivative (Pt^IV56OSS) were synthesized and successfully characterised via NMR spectroscopy, HPLC, ESI-MS, UV, and CD spectroscopy. The cytotoxic activity of Pt^II56OSS and Pt^IV56OSS against A549, A375 and MDA-MB-231 cancer cells was investigated, and the results showed that both complexes exhibit dose dependent growth inhibition against all three cancer cell lines. In addition, Pt^IV56OSS displayed significantly less toxicity against mesenchymal cells (MCs; >100 μM) compared to both Pt^II56OSS (6.5 μM) and cisplatin (2.0 μM). A Dose Escalation Study on Balb/c mice showed that the most tolerated dose (MTD) for Pt^II56OSS and Pt^IV56OSS were 140 and 200 mg/kg.b.w., respectively (which were ∼23-fold and 33-fold more tolerated than cisplatin). Cellular uptake experiments in A549 cells after 1, 3, 6, 12, 24 and 30 h of incubation, showed that both complexes are actively transported into the cells with Pt^II56OSS exhibiting a similar uptake rate to cisplatin and approximately a 3-fold higher uptake than Pt^IV56OSS. Intracellular distribution showed that while Pt^II56OSS resides primarily in the Cytoplasmic Fraction) while (CF), the Pt^IV56OSS resides heavily in the nucleus and cytoskeleton (NC) fraction. A549 cells treated with Pt^II56OSS and Pt^IV56OSS also showed a significant increase in the production of cellular ROS at all-time points (24, 48 and 72 h). Flow cytometry results demonstrated that Pt^II56OSS and Pt^IV56OSS caused significant increase in apoptotic cell death. Western blot assays exhibited an upregulation of cytochrome c, cleaved Parp, and the ratio of Bax/Bcl-2 when A549 cells were treated with either Pt^II56OSS and Pt^IV56OSS. These results distinguish Pt^II56OSS and Pt^IV56OSS as promising candidates for further investigation both in vitro and in vivo against several cancer models with the platinum(IV) analogue showing more promise due to its low cytotoxicity against normal cells coupled with its high in vivo tolerability.

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环氧取代多芳族铂（II）和铂（IV）配合物对A549肺癌细胞的抗肿瘤作用

合成了一种新型铂（II）配合物PtII56OSS，配合物为5,6-环氧-5,6-二氢-1,10-菲罗啉及其铂（IV）二羟基衍生物（PtII56OSS），并通过NMR、HPLC、ESI-MS、UV和CD光谱成功地对其进行了表征。研究了PtII56OSS和PtIV56OSS对A549、A375和MDA-MB-231癌细胞的细胞毒活性，结果表明，这两种复合物对三种癌细胞都表现出剂量依赖性的生长抑制作用。此外，PtIV56OSS对间充质细胞（MCs）的毒性显著降低；比;与PtII56OSS （6.5 μM）和顺铂（2.0 μM）相比，PtII56OSS （6.5 μM）和顺铂（2.0 μM）均有明显的差异。Balb/c小鼠剂量递增研究显示，PtII56OSS和PtIV56OSS的最大耐受剂量（MTD）分别为140和200 mg/kg.b.w。（分别比顺铂耐受性高23倍和33倍）。A549细胞在孵育1、3、6、12、24和30小时后的细胞摄取实验表明，这两种复合物都被积极地转运到细胞中，PtII56OSS的摄取率与顺铂相似，大约是PtII56OSS的3倍。细胞内分布显示，PtII56OSS主要存在于细胞质部分（Cytoplasmic Fraction），而（CF）， PtII56OSS主要存在于细胞核和细胞骨架（NC）部分。PtII56OSS和PtIV56OSS处理的A549细胞在24、48和72小时的时间点上也显示细胞ROS的产生显著增加。流式细胞术结果显示，PtII56OSS和PtIV56OSS可显著增加凋亡细胞的死亡。Western blot检测显示，PtII56OSS和PtIV56OSS处理A549细胞时，细胞色素c、裂解Parp和Bax/Bcl-2比值上调。这些结果将PtII56OSS和PtIV56OSS区分为有希望的候选者，在体外和体内对几种癌症模型进行进一步的研究，其中铂（IV）类似物由于其对正常细胞的低细胞毒性以及高体内耐受性而显示出更大的希望。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.