Ruthenium(II)/(III) DMSO-Based Complexes of 2-Aminophenyl Benzimidazole with In Vitro and In Vivo Anticancer Activity

Abstract

New anticancer ruthenium(II/III) complexes [RuCl2(DMSO)2(Hapbim)] (1) and [RuCl3(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been synthesized and characterized, and their chemotherapeutic potential evaluated. The interaction of the compounds with DNA was studied by both UV-Visible and fluorescence spectroscopies, revealing intercalation of both the Hapbim ligand and the Ru complexes. The in vitro cytotoxicity of the compounds was tested on human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2), with compound (2) the most potent against cancer cells. The cytotoxic effect of (2) is shown to correlate with the ability of the Ru(III) complex to induce apoptosis and to cause cell-cycle arrest in the G2/M phase. Notably, both compounds were inactive in the noncancerous cell line. The anticancer effect of (2) has also been studied in an EAC (Ehrlich Ascites Carcinoma) mouse model. Significantly, the activity of the complex was more pronounced in vivo, with removal of the cancer burden at doses that resulted in only low levels of hepatotoxicity and nephrotoxicity. An apoptosis mechanism was determined by the observation of increased Bax and caspase 3 and decreased Bcl2 expression. Furthermore, (2) decreased oxidative stress and increased the levels of antioxidant enzymes, especially SOD, suggesting the enhancement of normal cell repair. Overall, compound (2) shows great potential as a chemotherapeutic candidate, with promising activity and low levels of side effects.

Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal

“…During recent decades, organometallic anticancer agents have emerged [4][5][6][7] as potential pharmaceutical options. More specifically, ruthenium compounds are considered the most promising drug candidates to date, because of their favorable kinetic properties, rich redox chemistry and high selectivity for cancer cells [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. In fact, several ruthenium complexes, such as the octahedral NAMI-A [23] or sodium trans-tetra-chloridobis(1Hindazole)ruthenate(III) (IT-139) [15,[24][25][26] complexes as well as arene-Ru(II) derivatives of the RAPTA family [27][28][29][30], containing the PTA ligand, or RM175 [31,32], have been complexes, such as the octahedral NAMI-A [23] or sodium trans-tetra-chloridobis(1Hdazole)ruthenate(III) (IT-139) [15,[24][25][26] complexes as well as arene-Ru(II) derivatives the RAPTA family [27][28][29][30], containing the PTA ligand, or RM175 [31,32], have been ev uated as chemotherapeutic agents in clinical trials (see Figure 1).…”

Benzimidazole based derivatives as anticancer agents: Structure activity relationship analysis for various targets

“…Elsayed et al [80] synthesized novel complexes of Ruthenium (II and III) namely, [Ru(II)Cl 2 (DMSO) 2 (Hapbim)] and [Ru(III)Cl 3 (DMSO)(Hapbim) and examined their in vitro anticancer activity against MCF‐7 (breast cancer) cell lines, human CRC cell lines as well as normal liver cell lines. Out of both, compound 57 that is, [Ru(III)Cl 3 (DMSO)(Hapbim), was found to exhibit most promising results with least toxic side effects due to the tendency of Ru (III) complex to cause apoptosis and arrest cell cycle progression in G2/M phase (Figure 15).…”

Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens

“…Although the complexes may demonstrate different anti-microbial activity [ 52 , 53 , 54 ], anticancer activity of such compounds is more predominant. Therefore, it is crucial to consider various pharmacological, excretion, metabolism, and toxicity properties while designing novel compounds [ 55 ].…”