Monofunctional dimetallic Ru(η6-arene) complexes inhibit NOTCH1 signaling pathway and synergistically enhance anticancer effect in combination with cisplatin or vitamin C

Na Wang; Amjad Ali; Zongwei Liu; Huiqin Chi; Zhimin Lv; Xing Zhao; Zeqing Zhang; Huifang Hao; Yongmin Zhang; Faiz-Ur Rahman

doi:10.1016/j.ejmech.2023.115536

Monofunctional dimetallic Ru(η6-arene) complexes inhibit NOTCH1 signaling pathway and synergistically enhance anticancer effect in combination with cisplatin or vitamin C

Eur J Med Chem. 2023 Oct 5:258:115536. doi: 10.1016/j.ejmech.2023.115536. Epub 2023 May 30.

Authors

Na Wang¹, Amjad Ali², Zongwei Liu¹, Huiqin Chi¹, Zhimin Lv¹, Xing Zhao¹, Zeqing Zhang¹, Huifang Hao³, Yongmin Zhang⁴, Faiz-Ur Rahman⁵

Affiliations

¹ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
² Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Peshawar, KPK, Pakistan; Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, People's Republic of China.
³ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China; School of Life Sciences, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
⁴ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France. Electronic address: yongmin.zhang@upmc.fr.
⁵ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China. Electronic address: faiz@imu.edu.cn.

PMID: 37295260
DOI: 10.1016/j.ejmech.2023.115536

Abstract

ONS donor ligands L1-L4 were utilized in the preparation of monofunctional dimetallic Ru(η6-arene) complexes (C1-C4). These ONS donor ligand based novel tricoordinated Ru(II) complexes bearing η6-arene co-ligand were prepared for the first time. The current methodology resulted in excellent isolated yields and these complexes were characterized in detail by different spectroscopic and spectrometric techniques. The structures of C1-C2 and C4 were characterized in solid state by single crystal X-ray analysis. The in vitro anticancer analyses showed these novel complexes suppressed the growth of breast (MCF-7), liver (HepG2) and lung (A549) cancer cells. C2 suppressed the growth of these cells in dose-dependent manner revealed form the MTT and crystal violet cell viability assays. Moreover, C2 was observed the most potent complex that was used further in detailed mechanistic analyses in cancer cells. C2 showed good cytotoxic activity at 10 μM dose level as compared to cisplatin or oxaliplatin in these cancer cells. We observed morphological changes in cancer cells upon treatment with C2. Moreover, C2 suppressed the invasion and migration ability of cancer cells. C2 induced cellular senescence to retard cell growth and suppressed the formation of cancer stem cells. Importantly, C2 showed synergistic anticancer effect in combination with cisplatin and Vitamin C to further inhibit cell growth which suggested the potential role of C2 in cancer therapy. Mechanistically, C2 inhibited NOTCH1 dependent signaling pathway to suppress cancer cell invasion, migration and cancer stem cells formation. Thus, these data suggested potential role of C2 in cancer therapy by targeting NOTCH1-dependent signaling to suppress tumorigenesis. The results obtained in this study for these novel monofunctional dimetallic Ru(η6-arene) complexes showed their high anticancer potency and this study will pave to further cytotoxicity exploration on this class of complexes.

Keywords: Metal anticancer complexes; NOTCH1 inhibition; Ru(II)-η6-arene complexes; Ru-(p-cymene); Tri-coordinated complexes.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Ascorbic Acid / pharmacology
Cell Line, Tumor
Cisplatin / pharmacology
Coordination Complexes* / chemistry
Coordination Complexes* / pharmacology
Drug Screening Assays, Antitumor
Ligands
Ruthenium* / chemistry
Ruthenium* / pharmacology
Signal Transduction

Substances

Cisplatin
Ascorbic Acid
Ligands
Antineoplastic Agents
Ruthenium
Coordination Complexes