A Select thiosemicarbazone copper(II) complex induces apoptosis in Gastric Cancer and targets Cancer Stem Cells reducing pluripotency markers.

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-10-23 DOI:10.1016/j.ejmech.2024.116994

David Fabra, Jorge Melones-Herrero, Javier Velazquez-Gutierrez, Ana I. Matesanz, Patricia D. Aliseda, Sofia Figueiras, Francisco Aguilar-Rico, Carmela Calés, Isabel Sánchez-Pérez, Adoracion G. Quiroga

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引用次数: 0

Abstract

Copper(II)-based complexes are promising candidates as anti-cancer agents due to their ability to target cancer cells. Here we describe the synthesis and characterization of two copper(II) thiosemicarbazone complexes with the ligands 4-(dimethylamino)benzaldehyde N4-methylthiosemicarbazone (HL¹) and 4-(dimethylamino)benzaldehyde N4-(4-(dimethylamino)phenylthiosemicarbazone (HL²) and general formula [Cu(L)₂]. The complexes show stability in aqueous solution with 1% of DMSO that allows to stablish its solution profile in biological buffers. Compound [Cu(L¹)₂] lipophilicity was lower than [Cu(L²)₂] however its solubility in biological buffer was not only better but also its DLS and z-potencial data. In vitro studies demonstrate a higher cytotoxic effect of [Cu(L¹)₂] on gastric cancer cells. The proposed mechanism of action consists in the generation of free radicals that induce DNA lesions, oxidative stress and ultimately autophagy deregulation and apoptosis. Additionally, [Cu(L¹)₂] is equally active on gastric cancer stem cells and tumor cells resistant to cisplatin. More importantly, stem cells treated with [Cu(L¹)₂] show a downregulation of pluripotency markers such as TWIST, NANOG and OCT4. Overall, our results with [Cu(L¹)₂] prompt a significant advancement in the development of rational-designed pharmaceuticals for combating cancer.

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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.