Karuppannan Natarajan

In order to find out the influence of carboxylic acid functionalities (COOH) present at different positions in 2,2′-bipyridine on various biological activities such as DNA/protein binding, antioxidant activity and cytotoxicity, three new ruthenium(II) complexes [RuCl₂(bpy)(S-DMSO)₂] (1) (bpy = 2,2′-bipyridine), [RuCl₂(H₂L1)(S-DMSO)₂] (2) (H₂L1 = 2,2′-bipyridine-4,4′-dicarboxylic acid) and [RuCl₂(H₂L2)(S-DMSO)₂] (3) (H₂L2 = 2,2′-bipyridine-5,5′-dicarboxylic acid) have been synthesized and structurally characterized by analytical and spectral methods. The structures of 1 and 3 have been determined by single crystal X-ray diffraction studies, which revealed that both are a roughly regular octahedron with bipyridine/bipyridine dicarboxylic acid as neutral bidentate donors with the involvement of both the nitrogen atoms of the bipyridine ring. In vitro DNA binding studies of the complexes were carried out employing absorption titrations, fluorescence spectra, thermal melting, viscosity and circular dichroic measurements, which disclosed that all the complexes bind to CT-DNA via groove binding. The interactions of the complexes with bovine serum albumin (BSA) were also investigated using UV-visible, fluorescence and synchronous fluorescence spectroscopic measurements. The results indicated that the new complexes quench the intrinsic fluorescence of BSA protein in a static quenching mode. The assessment of free radical scavenging ability involving the DPPH radical, hydroxyl radical, nitric oxide radical, superoxide anion radical, and hydrogen peroxide and a metal chelating assay showed that the new complexes 2 and 3 possess excellent radical scavenging properties over 1 and standard antioxidants vitamin C and BHT. The in vitro cytotoxic activity of the new ruthenium complexes has been validated against HCT-15, HeLa, SKOV3, MCF7 and SKMel2 human cancer cells by SRB assay and cytotoxic selectivity has been examined against NIH 3T3 and HEK 293 normal cells by MTT assay and compared with that of the ruthenium anticancer drug NAMI A and standard platinum drug, cisplatin. The results indicated that the new complexes 2 and 3 displayed substantial cytotoxic specificity towards cancer cells only. Incorporation of a carboxylic acid group in the bipyridine moiety has resulted in showing differences in DNA/protein binding affinity, efficiency in antioxidant activity and cytotoxicity.

To gain some insight into the influence of chelation on anticancer activities, two new bivalent organometallic ruthenium complexes, [Ru(L)Cl(CO)(PPh₃)₂] (3) and [Ru(L)Cl(CO)(AsPh₃)₂] (4), (HL = 2,5-di(1H-pyrazol-1-yl)-1,4-benzoquinone) were synthesized, structurally characterized comprehensively by elemental analysis, IR, electronic, ¹H/¹³C NMR spectral studies and their biological activities (DNA/protein interactions, antioxidant and cytotoxic activity studies) have been investigated and compared with that of appropriate precursor complexes [RuHCl(CO)(PPh₃)₃] (1), [RuHCl(CO)(AsPh₃)₃] (2) and the ligand LH. The crystal structures of both the new complexes 3 and 4 were determined by single crystal X-ray diffraction studies, which unveil that the central ruthenium ion adopted distorted octahedral geometry with L as a monobasic bidentate donor and the chelator was observed to undergo C–H activation at one of the ortho positions leading to the formation of a five-membered metallacycle. DNA/protein interactions of the complexes have been examined by photophysical studies, which demonstrated a non-intercalative binding mode of the complexes with DNA and the complexes strongly quench the fluorescence intensity of bovine serum albumin (BSA) through the mechanism of static quenching. The new complexes demonstrated better binding affinity with DNA/protein. The compounds were evaluated for their free radical scavenging ability involving DPPH radicals, hydroxyl radicals, nitric oxide radicals, superoxide anion radicals and hydrogen peroxide. The results showed that the new complexes 3 and 4 possess significant radical scavenging ability and outperform the standard antioxidants vitamin C and BHT. The results of in vitro cytotoxicity of the complexes tested against B16F10, HeLa, A549, MCF7 and SKOV3 cells by SRB assay were compared with the standard drug cisplatin and that the new complexes 3 and 4 showed better activity in inhibiting the growth of the cancer cells. The influence of chelation was seen in all the biological activities studied and the new ruthenium chelates 3 and 4 were found to be superior to the precursor complexes 1, 2 and the ligand LH in DNA/protein binding properties, radical scavenging ability and cytotoxicity.

Two new ruthenium(II) carbonyl complexes have been synthesized from [RuHCl(CO)(PPh₃)₃] and 2-hydroxy-1-naphthaldehydethiosemicarbazone [H₂-(Nap-tsc)]. The stoichiometric reaction afforded two different complexes (1 and 2) exhibiting different structural motifs. In complex 1, the ligand coordinated through the N(2) nitrogen and thiolate sulphur by forming a strained four member chelate ring by leaving three donor sites (phenolic oxygen, N1 nitrogen and terminal nitrogen) uncoordinated. However, in complex 2, it coordinated as an ONS tridentate with the formation of a six member and a five member ring. In order to utilize the three unutilized donor sites in complex 1, it was reacted further with [NiCl₂(PPh₃)₂], which resulted in the formation of a new hetero bimetallic complex 3 wherein all the donor atoms of the ligand were utilized. The complexes have been characterized analytically and spectroscopically and X-ray diffraction (1, 3) and have also been evaluated for their binding affinity with HS-DNA. The electrostatic binding of the complexes with DNA was evident from absorption and fluorescence titration experiments. The binding interaction between the complexes 1–3 and bovine serum albumin (BSA) was studied by absorption, fluorescence and synchronous spectra at room temperature. From the results, it is inferred that complex 2 had a better binding ability with the tryptophan residues of BSA. The mechanism of complex interaction was found as static quenching. The in vitro cytotoxicity of metal complexes (1–3) has been evaluated by colorimetric assay (MTT assay).

The reaction of [RuHCl(CO)(PPh₃)₃] with an equimolar amount of salicylaldehyde-4(N)-methylthiosemicarbazone [H₂-(Sal-mtsc)] resulted in two entities, namely [Ru(H-Sal-mtsc)Cl(CO) (PPh₃)₂] (1) and [Ru(Sal-mtsc)(CO)(PPh₃)₂] (2) from a single tub. The new complexes were characterized by various spectro (IR, absorption and NMR), analytical and single crystal X-ray diffraction studies. From the crystallographic studies, it is confirmed that in complex 1, the ligand coordinated through the thiolate sulfur and the deprotonated hydrazinic nitrogen N(2), resulting in the formation of an unusual strained four membered chelate ring. The third potential donor, phenolic oxygen, remained uncoordinated. In complex 2, the ligand coordinated as an ONS chelate with the formation of more common five and six membered chelate rings. Complexes 1 and 2 have been tested for their DNA/protein binding properties by taking CT-DNA/lysozyme as models. From the protein binding studies, the alterations in the secondary structure of lysozyme by the ruthenium(II) complexes (1 and 2) were confirmed with synchronous and three-dimensional fluorescence spectroscopic studies. The in vitro cytotoxicity of the newly-synthesized complexes was carried out in two different human tumour cell lines, A549 and HepG2. The cytotoxicity studies showed that complex 2 exhibited higher activity than 1.

Two new bivalent organometallic ruthenium complexes [Ru(HL)(CH₃CN)(CO)(PPh₃)₂] (3) and [Ru(HL)(CH₃CN)(CO)(AsPh₃)₂] (4), (HL = 4-oxo-4H-pyran-2,6-dicarboxylic acid) were synthesized, structurally characterized and their biological activities (anti-microbial, DNA–protein interactions, antioxidant and cytotoxic activity studies (MTT, LDH release and NO release)) have been investigated and compared with that of appropriate precursor complexes [RuHCl(CO)(PPh₃)₃] (1), [RuHCl(CO)(AsPh₃)₃] (2) and the ligand H²L. The crystal structure of the complex 3 was solved by a single crystal X-ray diffraction technique, which revealed that it is a distorted octahedral with HL as a dibasic bidentate donor and the chelator was observed to undergo C–H activation at one of the ortho positions, leading to the formation of a five membered metallacycle. The in vitro antimicrobial activity was carried out using the well diffusion method against different species of pathogenic bacteria and fungi and complex 4 exhibited a better activity in inhibiting the growth of the tested organisms. DNA–protein interactions of the complexes have been examined by photophysical studies, which revealed that the complexes can bind with DNA through non-intercalation and the complexes strongly quench the intrinsic fluorescence of bovine serum albumin, through a static quenching process. The free radical scavenging ability, assessed by a series of in vitro antioxidant assays involving the DPPH radical, hydroxyl radical, nitric oxide radical, superoxide anion radical, hydrogen peroxide and a metal chelating assay showed that the new complexes 3 and 4 possess excellent radical scavenging properties over 1, 2, H²L, and the standard drugs, vitamin C and BHT. The in vitro cytotoxic activities of the compounds have been validated against A549 cells via an MTT assay, LDH release, NO release and the values were compared with that of the standard drug cisplatin. The results indicated that the new complexes, specifically the complex 3, displayed a higher cytotoxic activity in inhibiting the growth of A549 cells, outperforming by five fold, the standard drug cisplatin.

Reaction of 2-hydroxy-1-naphthaldehyde-4(N)-ethylthiosemicarbazone [H₂-(Nap-etsc)] with [RuHCl(CO)(PPh₃)₃] conferred two entities, namely [Ru(H-Nap-etsc)Cl(CO)(PPh₃)₂] (1) and [Ru(Nap-etsc)(CO)(PPh₃)₂]·Cl (2). The new complexes were characterized using various spectroanalytical and X-ray crystallographic techniques. In this reaction the dual coordination behaviour (thiolate/thione) of the ligand was observed. It acted as NS bidentate monobasic and ONS tridentate monobasic in entities 1 and 2 respectively. The binding ability of complexes (1 and 2) to calf thymus DNA (CT DNA)/BSA has been explored by absorption and emission titration methods. The cytotoxic nature of the complexes was evaluated on human lung cancer cells, A549. Complexes induced apoptotic cell death via ROS hypergeneration and mitochondrial membrane damage. In addition these newly synthesized ruthenium complexes inhibited A549 cell migration, as evidenced by wound healing assay. The activity of the complexes was found to be very high by comparing with cisplatin, a conventional standard. The time dependent release of the complexes from porous system was investigated by taking mesoporous silica as the host material. It was shown that the main portion of the embedded complexes was released after 20 h and reached a maximum after 96 h.

A series of four new palladium(II) complexes of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones with triphenylphosphine as coligand have been synthesized and characterized by the aid of various spectral techniques. The single-crystal X-ray diffraction studies revealed that the unsubstituted thiosemicarbazone ligand acted as monobasic tridentate (ONS^–) in the cationic [Pd(H-Qtsc-H)(PPh₃)]Cl complex, whereas the monosubstituted thiosemicarbazone ligands acted as monobasic bidentate (NS^–) in their respective complexes, [PdCl(H-Qtsc-R)(PPh₃)] (R = Me (2), Et (3), Ph (4)). To ascertain the potentials of the above Pd(II) complexes toward biomolecular interactions, additional experiments involving interaction with calf thymus DNA and bovine serum albumin were carried out. Moreover, all the palladium(II) complexes have been screened for their radical scavenging activity toward DPPH, O₂^–, OH, and NO radicals. The efficiency of the complexes in arresting the growth of human cervical cancer cells (HeLa), human laryngeal epithelial carcinoma cells (HEp-2), human liver carcinoma cells (Hep G2), and human skin cancer cells (A431) has also been studied along with the cell viability test against the noncancerous NIH 3T3 mouse embryonic fibroblasts cell lines under in vitro conditions. All the in vitro pharmacological evaluation results clearly revealed the relationship between the structure and the activity of the new Pd(II) complexes.

Three new nickel(II) thiosemicarbazone complexes have been synthesized and characterized by analytical, spectral, and single-crystal X-ray diffraction studies. In complex 1, the ligand 2-hydroxy-1-naphthaldehydethiosemicarbazone coordinated as a monobasic tridentate donor, whereas in complexes 2 and 3, the ligands salicylaldehyde-4(N)-ethylthiosemicarbazone and 2-hydroxy-1-naphthaldehyde-4(N)-ethylthiosemicarbazone coordinated as a dibasic tridentate donor. The DNA binding ability of the complexes in calf thymus DNA was explored by absorption and emission titration experiments. The antioxidant property of the new complexes was evaluated to test their free-radical scavenging ability. In vitro cytotoxicity assays were performed for the new complexes in A549 and HepG2 cell lines. The new compounds overcome cisplatin resistance in the A549 cell line and they were also active in the HepG2 cell line. The cellular uptake study showed the accumulation of the complexes in tumor cells depended on the nature of the ligand attached to the nickel ion. Structurally different nickel(II) thiosemicarbazone complexes for which DNA binding, antioxidant, cytotoxicity, and cellular uptake studies were performed