Ruthenium(II) Complexes of Isothiazole Ligands: Crystal Structure, HSA/DNA Interactions, Cytotoxic Activity and Molecular Docking Simulations

Abstract

Two new neutral ruthenium(II) complexes [Ru(η 6-p-cymene) Cl 2 (1)] (3) and [Ru(η 6-p-cymene)Cl 2 (2)] (4) (1 = 5-(phenylamino)-3-pyrrolidin-1-ylisothiazole-4-carbonitrile; 2 = 3-morpholin-4-yl-5-(phenylamino)isothiazole-4-carbonitrile) have been synthesized and characterized using elemental analysis, IR, UV-Vis and NMR spectroscopy. The crystal structure was confirmed for complex 3 and both ligands. Examination of the interactions of ligands and complexes with CT-DNA (Calf Thymus DNA), as well as with HSA (Human Serum Albumin) revealed that ligands and complexes could interact with CT-DNA through intercala-tion and could bind strongly with HSA. Docking experiments toward DNA dodecamer indicate excellent accordance with experimental ΔG values. The cytotoxic activity of ligands and complexes was evaluated by MTT assay against HCT116 and HeLa tumoral cells. The complexes 3 and 4 showed good activity and selectivity on HCT116 cells. Neither of the tested compounds shows cytotoxic activity against a healthy MRC-5 cell line. Flow cytometry analysis showed the apoptotic death of the HCT116 cells with a cell cycle arrest in the S-phase.

Search for new biologically active compounds: in vitro studies of antitumor and antimicrobial activity of dirhodium(ii,ii) paddlewheel complexes

“…86 Compounds that can intercalate into DNA with similar or higher affinity as EB significantly reduce the emission of EB–DNA systems, as they can completely replace EB, whereas compounds that behave as groove binders can only partially replace EB in these systems, resulting in a moderate reduction in the emission of EB–DNA solutions. 15,87,88…”

“…UV-Vis absorption spectroscopy is a widely used and effective method in DNA binding studies. 15,88 The changes observed in the UV spectra (hypochromism/hyperchromism and/or red shift/blue shift) during titration can provide clues to the nature of the interaction between complexes and DNA. 27 Indeed, the hypochromic effect together with the bathochromic effect (red shift) usually occurs when the intercalative binding mode of the complex to DNA is involved, while the electrostatic binding mode is expressed by the hyperchromic effect.…”

“…In addition, many promising coordination compounds are now in clinical use to cure numerous tumors. 14–24 Apart from this, dirhodium( ii , ii )–tetracarboxylate complexes are of great interest due to their proven antitumor activity and minimal side effects. 17,25–31 Interest in this type of metal–metal complexes began in the 1970s when Bear and coworkers first demonstrated the potential cytostatic activity of complexes of the formula [Rh 2 (μ-OOCR) 4 ] (R = Me, Et, Pr).…”