Ruthenium(II) complexes of saccharin with dipyridoquinoxaline and dipyridophenazine: Structures, biological interactions and photoinduced DNA damage activity

• Published in: European journal of medicinal chemistry 2017-08, Vol.136, p.52-62
• Main Authors: Kumar, Priyaranjan, Dasari, Srikanth, Patra, Ashis K.
• Format: Article
• Language: English
• Subjects: Animals; Bioinorganic chemistry; Cattle; DNA - drug effects; DNA and BSA binding; DNA Damage; DNA photocleavage; Dose-Response Relationship, Drug; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Phenazines - chemistry; Phenazines - pharmacology; Photochemical Processes; Quinoxalines - chemistry; Quinoxalines - pharmacology; Ruthenium - chemistry; Ruthenium - pharmacology; Ruthenium complexes; Saccharin; Saccharin - chemistry; Saccharin - pharmacology; Structure-Activity Relationship; Ultraviolet Rays
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.04.076

Ruthenium complexes trans-[Ru(sac)2(dpq)2] (1) and trans-[Ru(sac)2(dppz)2] (2) where sac is artificial sweetener saccharin (o-sulfobenzimide; 1,2-benzothiazole-3(2H)-one1,1-dioxide (Hsac)), dpq = dipyrido[3,2-d:2′,3′-f]quinoxaline and dppz = dipyrido[3,2-a:2′,3′-c]phenazine have been synthesized and thoroughly characterized using various analytical and spectral techniques. Saccharin known to act as carbonic anhydrase IX (CA IX) inhibitor which is a biomarker for highly aggressive and proliferative tumor in hypoxic stress, so inhibition of CA IX is a potential strategy for anticancer chemotherapy. The solid state structures, photophysical properties, photostability, DNA and protein binding affinity, and DNA photocleavage activity were explored. The structural analysis revealed Ru(II) centre is in discrete mononuclear, distorted octahedral {RuN6} coordination geometry with two monoanionic nitrogen donor saccharinate ligands and two neutral bidentate nitrogen donors ligands dpq and dppz. cis-[Ru(sac)2(dppz)2] (cis-2) geometrical isomer was also isolated and structurally characterized by X-ray crystallography. The photo-induced dissociation of monodentate saccharin ligand is observed when irradiated at UV-A light of 365 nm. The complexes show significant binding affinity to the calf thymus DNA (Kb ∼ 105 M−1) through significant intercalation through planar dpq and dppz ligands. Interaction of complexes 1 and 2 with bovine serum albumin (BSA) showed remarkable tryptophan emission quenching (KBSA ∼105 M−1). The complexes showed appreciable photoinduced DNA cleavage activity upon irradiation of low power UV-A light of 365 nm from supercoiled (SC) to its nicked circular (NC) form at micromolar complex concentrations. Photocleavage mechanistic studies in presence of O2 reveals involvement of reactive oxygen species (ROS) mediated through ligand-centered 3ππ* and/or 3MLCT excited states generated upon photoactivation leads to nicking of supercoiled DNA to nicked circular form. In absence of O2, we also observed photocleavage of DNA through formation of photoinduced ligand dissociated Ru-DNA complex involving PACT pathway. [Display omitted] •Synthesis and characterization of trans-[Ru(sac)2(dpq/dppz)2] (1, 2) complexes.•The complexes show efficient binding interaction with DNA and BSA.•Photo-induced ligand dissociation of saccharin observed in UV-A light for 1 and 2.•DNA photocleavage via formation of ROS and PACT mechanism in anaerobic condition.•Saccharin as CA-IX