Dimetallic Ru(II) arene complexes appended on bis-salicylaldimine induce cancer cell death and suppress invasion via p53-dependent signaling

• Published in: European journal of medicinal chemistry Vol. 157; pp. 1480 - 1490
• Main Authors: Rahman, Faiz-Ur, Bhatti, Muhammad Zeeshan, Ali, Amjad, Duong, Hong-Quan, Zhang, Yao, Ji, Xinjian, Lin, Yuejian, Wang, Hui, Li, Zhan-Ting, Zhang, Dan-Wei
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.09.2018; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; bis-Salicylaldimine; Cell Death - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemistry, Medicinal; Dimetallic complexes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Molecular Structure; Neoplasm Invasiveness - pathology; Neoplasm Invasiveness - prevention & control; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pharmacology & Pharmacy; Ru(II) anticancer complexes; Ru-(p-cymene); Ru-anticancer complexes; Ruthenium - chemistry; Ruthenium - pharmacology; Science & Technology; Signal Transduction - drug effects; Structure-Activity Relationship; Tumor Suppressor Protein p53 - metabolism; Ru(II) anticancer complexes; Dimetallic complexes; bis-Salicylaldimine; Ru-anticancer complexes; Ru-(p-cymene); ANTIPROLIFERATIVE ACTIVITY; COPPER-COMPLEXES; PHOTODYNAMIC THERAPY; ESCHERICHIA-COLI; CISPLATIN RESISTANCE; IN-VITRO CYTOTOXICITY; ORGANOMETALLIC ANTICANCER COMPLEXES; LIGANDS SYNTHESIS; RUTHENIUM COMPLEXES; MOLECULAR-MECHANISMS
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.054

A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))2(bis-salicylaldimine)Cl2 (C1C4) were prepared. These complexes were obtained in excellent isolated yields and characterized in detail by using different spectroscopic techniques. The structure of C1 was also determined in solid state by single crystal X-ray analysis. These complexes were studied for their cytotoxic effect against three different types of human cancer cells including hepatocellular carcinoma (HepG2), non-small-cell lung cancer (A549) and breast cancer (MCF-7) cells by MTT assay. These complexes showed considerable cytotoxic effect in all the above-mentioned cell lines that was comparable to the effect of cisplatin. C1 and C2 showed moderate anticancer effect while C3 and C4 showed reasonable cytotoxicity. We found the cytotoxicity was increased in series from C1 to C4 representing the effect of ligand modification from small to bulky group at the amine functionality of the salicylaldimine. We selected C3 and C4 for mechanistic anticancer study in MCF-7 cells. The acridine orange/ethidium bromide and DAPI staining assays of MCF-7 cells treated with Ru(II) complexes showed apoptosis in cancer cells. Similarly, these complexes induced p53 protein expression in MCF-7 cells. Further, increased mRNA levels of p63, p73, PUMA, BAX and NOXA genes were observed in response to the treatment with C3 and C4, while cyclinD1, MMP3 and ID1 gene expression was significantly reduced. We found reduced invasion ability in breast cancer cells treated with C3 and C4. Taken together, we demonstrated that bis-salicylaldimine based dimetallic Ru-(p-cymene) complexes exerts anticancer effects by p53 pathway, suggesting the promising chemotherapeutic potentials of these Ru(II) complexes for the treatment of cancer. This study may further pave for their in depth in vitro or in vivo anticancer investigations. Dimetallic bis-salicylaldimine based Ru(II) arene complexes (Ru (p-cymene))2 (bis-salicylaldime)Cl2 were prepared and investigated as anticancer agents. Their in vitro cytotoxic effect on cancer cells was comparable to cisplatin. They induced p53, p63 and p73 genes expression and regulated PUMA, BAX and NOXA genes in MCF-7 breast cancer cells. [Display omitted] •Dimetallic ruthenium complexes.•Single crystal X-ray structure characterization.•Anticancer study of Ru(II) arene complexes.•Genes activation for efficient apoptosis in cancer cell.•p53 activation by Ru(II) complexes.