Nataraj Chitrapriya

Synthesis, characterization, DNA interaction, antioxidant and anticancer activity of new ruthenium(II) complexes of thiosemicarbazone/semicarbazone bearing 9,10-phenanthrenequinone.

A new series of octahedral ruthenium(II) complexes supported by tridentate ligands derived from phenanthrenequinone and derivatives of thiosemicarbazide/semicarbazide and other co-ligands have been synthesized and characterized. DNA binding experiments indicated that ruthenium(II) complexes can interact with DNA through non-intercalation and the apparent binding constant value (Kb) of [RuCl(CO)(PPh₃)(L₃)] (3) at room temperature was calculated to be 2.27 × 10(3)M(-1). The DNA cleavage studies showed that the complexes have better cleavage of pBR 322 DNA. Antioxidative activity proved that the complexes have significant radical scavenging activity against free radicals. Cytotoxic activities showed that the ruthenium(II) complexes exhibited more effective cytotoxic activity against selected cancer cells.

Bioconjugation of L-3,4-Dihydroxyphenylalanine Containing Protein with a Polysaccharide

We describe the simple bioconjugation strategy in combination of periodate chemistry and unnatural amino acid incorporation. The residue specific incorporation of 3,4-dihydroxy-l-phenylalanine can alter the properties of protein to conjugate into the polymers. The homogeneously modified protein will yield quinone residues that are covalently conjugated to nucleophilic groups of the amino polysaccharide. This novel approach holds great promise for widespread use to prepare protein conjugates and synthetic biology applications.

Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors

In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) polypeptide nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The smart pH-sensitive nanovehicle was fabricated with precisely tailored drug-to-carrier ratio that resulted in accelerated, sequential drug release. As a result of ratiometric loading, QUR could significantly enhance the cytotoxic potential of DOX, induced marked cell apoptosis; change cell cycle patterns, inhibit the migratory capacity of sensitive and resistant cancer cells. In particular, pro-oxidant QUR from DQ-NV remarkably reduced the GSH/GSSG ratio, indicating high oxidative stress and damage to cellular components. DQ-NV induced tumor shrinkage more effectively than the single drugs in mice carrying subcutaneous SCC-7 xenografts. DQ-NV consistently induced high expression of caspase-3 and PARP and low expression of Ki67 and CD31 immunomarkers. In summary, we demonstrate the development of a robust polypeptide-based intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy. STATEMENT OF SIGNIFICANCE In this study, we report a facile method to construct bioactive and biodegradable polypeptide nanovehicles as an advanced platform technology for application in cancer therapy. We designed a robust (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The conformational changes of the histidine block at tumor pH resulted in accelerated, sequential drug release. QUR could significantly enhance the cytotoxic potential of DOX, induce marked cell apoptosis, change cell cycle patterns, and inhibit the migratory capacity of sensitive and resistant cancer cells. DQ-NV induced tumor shrinkage more effectively than the single drugs and the 2-drug cocktail in tumor xenografts. In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.

Evaluation of DNA-binding, radical scavenging and cytotoxic activity of five coordinated Cd(II) complexes containing 2-acetylpyridine-N4-substituted thiosemicarbazone

A series of new five coordinated Cd(II) complexes of the type [Cd(Ln)Cl2] (n = 1–3) have been isolated and characterized using analytical, spectral and structural methods. The single crystal X-ray structure of one of the complexes [Cd(L2)Cl2] (2) has been determined and a distorted square pyramidal geometry has been found, in which Cd(II) is coordinated with two nitrogens, one sulfur and two chlorine atoms. The interactions of the complexes with calf thymus DNA (CT-DNA) have been explored by absorption, competitive, thermal denaturation and viscometric methods, which revealed that the compounds could interact with CT-DNA through groove binding. Investigation of the antioxidant properties showed that the Cd(II) complexes have a strong radical scavenging tendency against DPPH˙, OH˙ and NO˙ radicals. Further, the cytotoxic effect of the compounds examined on a human breast cancer cell line (MCF-7) showed that the complexes exhibited substantial cytotoxic activity.

Ligand effect and cooperative role of metal ions on the DNA cleavage efficiency of mono and binuclear Cu(II) macrocyclic ligands complexes.

Two binuclear Cu(II) complexes of N-functionalized macrocycle ligands, namely 1,3-bis(1,4,7-triaza-1-cyclonomyl)propane and 1-(3-(1,4,7-triazonan-1-yl)propyl)-1,4,7,10-tetraazacyclo-dodecane, were synthesized and their ability to hydrolyze the cleavage of supercoiled plasmid DNA (pBR322) was compared with that of structurally related non-functionalized mononuclear Cu(II) complexes. The former, binuclear Cu(II) complex with the symmetrical ligand exhibited enhanced double-strand cleavage activity compared to the other three complexes at the same [Cu(2+)] concentration. In contrast, the latter binuclear complex with unsymmetrical macrocylic ligand did not give rise to double-strand DNA cleavage. The linear DNA formation induced by the mononuclear Cu(II) 1,4,7,10-tetraazacyclo-dodecane complex was realized via a non-random double-stranded scission process. The differential cleavage activity is discussed in relation to dimer formation, effective cooperation and coordination environment of the metal center. The hydrolytic cleavage by the copper complexes without H2O2 is supported by evidence from an anaerobic reaction, free radical quenching, and nitro blue tetrazolium assay. In contrast, both the binuclear complexes cleaved supercoiled DNA efficiently to Form III (linearized DNA) in the presence of H2O2, indicating that nuclearity is a crucial parameter in oxidative cleavage. The radical scavenger inhibition study and nitro blue tetrazolium assay suggested the involvement of H2O2 and superoxide ions in the oxidative cleavage of DNA by the binuclear complexes.

Synthesis, DNA binding profile and DNA cleavage pathway of divalent metal complexes

Complexes of dipyridylamine based ligand with an anthracene moiety containing divalent metal ions Co(II), Cu(II), Ni(II), Zn(II) and Cd(II) were characterized structurally. The experimental results showed that they can induce considerable oxidative DNA cleavage in the presence of hydrogen peroxide and dioxygen. The Zn(II) complex did not show any appreciable cleavage activity, whereas the Cd(II) and Ni(II) complexes were moderately active. On the other hand, Cu(II) and Co(II) complex showed the formation of a significant quantity of linear DNA resulting from the double-strand breaks. Mechanistic studies revealed the involvement of HO˙ and the superoxide anion to be the reactive species in the scission process in aerobic media. A mechanism involving either the Fenton or the Haber–Weiss reaction was proposed for the DNA cleavage mediated by these complexes. The Cu(II) complex could also cleave the double stranded calf thymus DNA (ds DNA) in the presence of activators, most likely via an oxidative mechanism, whereas the activity of the other complexes was negligible under similar reaction conditions. The kinetic aspects of ds DNA cleavage with the Cu(II) are detailed. The interaction of the five metal complexes with ds DNA was investigated by UV absorption and linear dichroism studies, and the mode of complexes binding to ds DNA is proposed.

The effect of incorporating carboxylic acid functionalities into 2,2′-bipyridine on the biological activity of the complexes formed: synthesis, structure, DNA/protein interaction, antioxidant activity and cytotoxicity

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.