Water soluble Ru(<scp>ii</scp>)–arene complexes of the antidiabetic drug metformin: DNA and protein binding, molecular docking, cytotoxicity and apoptosis-inducing activity

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Two organometallic Ru(II)‐p‐cymene complexes of the type [Ru(η6‐p‐cymene)(L)Cl]PF6 1 and 2, where L is N,N‐bis(4‐isopropylbenzylidene)ethane‐1,2‐diamine (bien, L1) or N,N‐bis (pyren‐2‐ylmethylene)ethane‐1,2‐diamine (bpen, L2) have been prepared and characterized well. Because of appended pyrenyl groups in coordinated bpen ligand, the complex 2 exhibits higher DNA and protein binding than complex 1 in which isopropylbenzyl groups are incorporated. Interestingly, the luminescent characteristic complex 2 is unique in displaying DNA cleavage after light activation by UVA light at 365 nm through oxygen dependent mechanism. AFM analysis attests the photo‐induced DNA fragmentation ability of complex 2. Also, the complex 2 cleaves the protein after light exposure in a non‐specific manner suggesting that it can act as a protein photo cleaving agent. In contrast to the trend of DNA and protein interaction of complexes, the complex 1 exhibits cytotoxic activity against human breast carcinoma (MCF‐7) and liver carcinoma (HepG2) with potency higher than that of complex 2 due to enhanced hydrophobicity of isopropyl groups present in p‐cymene and bien ligands. Indeed, complex 2 is inactive against MCF‐7 and HepG2 cancer cell lines even up to 200 μM concentration. The AO/EB staining assay reveals that the complex 1 is able to induce late apoptotic mode of cell death in breast cancer cells, which is further confirmed by inter‐nucleosomal DNA cleavage. Furthermore, the complexes 1 and 2 are evaluated for their catalytic activities and found to be working well for the β‐carboline directed C–H arylation to afford the desired products in good yield (40–47%).

Section: Resultsmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biological and catalytic evaluation of Ru(II)‐p‐cymene complexes of Schiff base ligands: Impact of ligand appended moiety on photo‐induced DNA and protein cleavage, cytotoxicity and C‐H activation

Gopalakrishnan

Srinath

Baskar

et al. 2018

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“…Recently, it was found that vanadyl complex with metformin shows potential synergistic insulin mimics, while platinum (IV) complex reveals antitumor activity . The interaction of Metformin with calf thymus DNA has been investigated by Nahid Shahabadi et al Recently DNA binding studies of water soluble ruthenium (II)‐arene complex with metformin hydrochloride (Met) as ligand have been studied …”

Section: Introductionmentioning

confidence: 99%

“…[16] The interaction of Metformin with calf thymus DNA has been investigated by Nahid Shahabadi et al [17] Recently DNA binding studies of water soluble ruthenium (II)-arene complex with metformin hydrochloride (Met) as ligand have been studied. [18] Metformin and its ternary complexes have received less attention in spite of their potential metal binding properties and promising applications. From our laboratories, we recently reported the synthesis, characterization and DNA binding studies of cobalt (II), copper (II) and oxovanadium (IV) complexes containing metformin as primary ligand and α-diimine/α-diamine as auxiliary ligands.…”

Section: Introductionmentioning

confidence: 99%

Chromium‐metformin ternary complexes: Thermal, DNA interaction and Docking studies

Shekhar

Vasantha

Kumar

et al. 2019

Three chromium ternary complexes with metformin (met) as a primary ligand and bipyridine (bipy) or ortho‐phenylenediamine (opda) or ortho‐phenanthroline (phen) as secondary ligand were synthesized. These complexes [Cr (Cl)2(Hmet)(bipy)]‐(1), [Cr (Cl)2(Hmet)(opda)]‐(2) and [Cr (Cl)2(Hmet)(phen)]‐(3) were characterized by LC–MS, elemental analysis, molar conductance, thermal analysis, infrared spectroscopy, electronic spectroscopy. The geometrical structures have been found to be octahedral. Degradation pattern of the compounds is shown by thermal studies. The Kinetic parameters‐ energy of activation (Ea), enthalpy (ΔH), entropy (ΔS) and free energy changes (ΔG) have been determined by thermogravimetric data. Coats‐Redfern integration method with thirteen kinetic models was used to calculate the kinetic and thermodynamic parameters for the degradation of all the complexes. The stabilities of the complexes were obtained from their molecular orbital structures from which the quantum chemical parameters were calculated using the HOMO‐LUMO energies. UV–Visible absorption, fluorescence, and viscosity measurements have been conducted to assess the interaction of the complexes with CT DNA. The complexes showed absorption hyperchromism in its UV–Vis spectrum with DNA. The binding constants Kb from UV–Vis absorption studies were 3.1x104, 4.4x104, 5x104 M−1 for 1, 2, 3 respectively and Stern–Volmer quenching constants (Ksq) from fluorescence studies were 0.137, 0.532, 0.631 for 1, 2, 3 respectively. Finally, viscosity measurements revealed that the binding of the complexes with CT‐DNA could be surface binding, mainly due to groove binding. The activity of complexes towards DNA cleavage decrease in the order of 3 > 2 > 1.The light switching properties of the complexes were also evaluated. The complexes were docked in to B‐DNA sequence, 5′(D*AP*CP*CP*GP*AP*CP*GP*TP*CP*GP*GP*T)‐3′ retrieved from protein data bank (PDB ID: 423D), using Discovery Studio 2.1 software.

Ruthenium(II)–arene complexes of diimines: Effect of diimine intercalation and hydrophobicity on DNA and protein binding and cytotoxicity

Ganeshpandian

Palaniandavar

Muruganantham

et al. 2017

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A series of half‐sandwich Ru(II)–arene complexes [Ru(η6‐benzene)(diimine)Cl](PF6) (1–4), where diimine is 1,10‐phenanthroline (1), 5,6‐dimethyl‐1,10‐phenanthroline (2), dipyrido[3,2‐a:2′,3′‐c]phenazine (3) or 11,12‐dimethyldipyrido[3,2‐a:2′,3′‐c]phenazine (4), have been isolated and characterized using analytical and spectral methods. Complex 2 possesses a familiar pseudo‐octahedral ‘piano‐stool’ structure. The intrinsic DNA binding affinity of the complexes depends upon the diimine ligand: 3 (dppz) > 4 (11,12‐dmdppz) > 2 (5,6‐dmp) > 1 (phen). The π‐stacking interaction of extended planar ring of coordinated dppz (3) in between the DNA base pairs is more intimate than that of phen (1), and the incorporation of methyl groups on the dppz ring (4) discourages the stacking interaction leading to a lower DNA binding affinity for 4 than 3. Docking studies show that all the complexes bind in the major groove of DNA. Interestingly, 3 shows an ability to convert supercoiled DNA into nicked circular DNA even at 20 μM concentration beyond which complete oxidative DNA degradation is observed. The protein binding affinity of the complexes decreases in the order 4 > 3 > 2 > 1, and the higher protein binding affinity of 4 illustrates the strong involvement of methyl groups on dppz ring in hydrophobic interaction with protein. Also, 4 cleaves protein more efficiently than the other complexes in the presence of H2O2. It is notable that 2, 3 and 4 display cytotoxicity against human cervical cancer cell lines (SiHa) with potency higher than the currently used drug cisplatin. Acridine orange/ethidium bromide staining studies reveal that 3 induces apoptosis in cancer cells much more efficiently than 4.