Heterodinuclear Ru-Pt Complexes Bridged with 2,3-Bis(pyridyl)pyrazinyl Ligands: Studies on Kinetics, Deoxyribonucleic Acid/Bovine Serum Albumin Binding and Cleavage, In Vitro Cytotoxicity, and In Vivo Toxicity on Zebrafish Embryo Activities.

Abstract

Di- and poly-homo/heteronuclear complexes have great potential as anticancer drugs. Here, we report their reactivity, deoxyribonucleic acid (DNA)/bovine serum albumin (BSA) binding and cleavage interactions, in vitro cytotoxicity, and in vivo zebrafish embryo toxicity of [(phen)2Ru(μ-L)PtCl2]2+ (phen = 1,10-phenanthroline and L = 2,3-bis(2-pyridyl)pyrazine, bpp, C1; 2,3-bis(2-pyridyl)quinoxaline, bpq, C2ial; 2,3-bis(2-pyridyl)benzo[g]quinoxaline, bbq, C3) anticancer prodrugs. The substitution reactivity increases from C1 to C3 owing to an increase in the π-conjugation on the bridging chelate which facilitates π-back bonding. As a result, the electrophilicity index on the C3 complex increases than that on the complex C2 followed by C1 which leads to higher rates of substitution and thus the reactivity order follows C1 < C2 < C3. The coordination of Ru at one end of each of the complexes enhances water solubility. Moreover, the charge addition of the two metal ions increases their reactivity toward substitution in addition to ensuring electrostatic interactions at target sites such as the DNA/BSA. Spectroscopic (UV–vis absorption and fluorescence quenching) titration and viscosity measurement results of the interactions of C1/2/3 with CT-DNA established the formation of stable, nonconvent C1/2/3-DNA adducts with DNA most likely via the intercalative binding mode. Furthermore, studies with BSA showed a good binding affinity of these complexes owing to hydrophobic interactions with the coordinated ligands. The interactions of these complexes with DNA/BSA are in line with the reactivity trend, and all these experimental findings were further supported by molecular docking analysis. In vitro MTT cytotoxic activities on human breast cancer cell line MCF-7 revealed that all the complexes have high cytotoxicity activity (IC50 > 9 μM); furthermore, the selectivity index and SI values were higher (>3). Complex C3 showed the highest cytotoxicity with IC50 = 3.1 μM and SI value (5.55) against MCF7 cell lines and these values were comparable to those of the cisplatin (IC50 and SI values are 5.0 μM and 4.02, respectively). In vivo toxicological assessments on zebrafish embryos revealed that all the Ru–Pt complexes (CI/2/3) have poor embryo acute toxic effects over 96 h postfertilization, hpf with LC50 > 65.2 μM. The complex C3 has shown the lowest embryo toxicity (LC50 = 148.8 μM), which is comparable to that of commercial cisplatin (LC50 = 181.1 μM). Based on the cytotoxicity results, complexes C2 and C3 could be considered for further development as chemotherapeutic agents against MCF breast cancer cells.