Novel ruthenium(II) triazine complex [Ru(bdpta)(tpy)]2+ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells.

Ruthenium(II/III) metal complexes have been widely recognized as the alternative chemotherapeutic agents to overcome the drug resistance and tumor recurrence associated with platinum derivatives. In this work, a novel ruthenium(II) triazine complex namely, 1 ([Ru(bdpta)(tpy)]2+) was synthesized and spectroscopically characterized. Drug resistant cancer stem cells (CSCs) were used to evaluate the cytotoxicity of Ru(II) complex 1. The complex 1 showed a greater cytotoxic potential with IC50 values lower than that of cisplatin. The intracellular localization assay confirmed that the complex 1 was effectively distributed into mitochondria as well as endoplasmic reticulum (ER), and executed a ROS-mediated calcium and Bax/Bak dependent intrinsic apoptosis. Interestingly, direct interaction between complex 1 and glucose regulated protein 78 (GRP78), a protein associated with drug resistance caused the ROS-mediated ubiquitination of GRP78. Notably, western blot and confocal microscopy analysis confirmed that complex 1 significantly reduced the protein levels of GRP78. Dose-dependent in vivo antitumor efficacy against CD133+HCT-116 CSCs derived tumor xenograft further validated that complex 1 could be an effective chemotherapeutic agent.

Metal complexes of isonicotinylhydrazide and their antitubercular activity.

The development and spreading of Multi Drug Resistant TB strains is hampering endeavours for the control and administration of tuberculosis (TB). The expansion episodes of multi-medication safe strains of Mycobacterium tuberculosis against first and second line antituberculosis drugs on one side and the unfavourable effects of these drugs on the other side has led the enthusiasm of researcher towards the synthesis of metal complexes of various medication. This approach is born with the expectation of finding new antituberculous operators without or least reactions as well as being active against the resistant strains of Mycobacterium tuberculosis. This study concentrates on the screening of five metal complexes of isoniazid (INH) against five Mycobacterium tuberculosis strains. These strains have been confirmed by WHO being active and even proliferating safely even in the presence of pyrazinamide, isoniazid (INH), ethambutol and rifampicin. In this work INH was taken as reference medication. All synthesized complexes and INH were subjected for a month and a half in BACTEC MGIT 960 technique. INH and its Fe (II) complex restrained the development of all bacterial strains for merely two weeks, while the Fe(III), Cu(II), Co (II) and Mn (II) complexes repressed the development five strains for three weeks. Conclusively, the strains utilized in this study were discovered to be more susceptible to the later four complexes than the ligand (INH) drug and its Fe (II) complex. Furthermore, elemental analysis and atomic absorption of all complexes were conducted for the determination of metal to ligand ratio.

Manganese Complex of Ethylenediaminetetraacetic Acid (EDTA)-Benzothiazole Aniline (BTA) Conjugate as a Potential Liver-Targeting MRI Contrast Agent.

A novel manganese(II) complex based on an ethylenediaminetetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn2+, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and R1 relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent. The diagnostic utility of this new Mn complex in MRI was demonstrated by high-sensitivity tumor detection in an animal model of liver cancer.

The Cu/ligand stoichiometry effect on the coordination behavior of aroyl hydrazone with copper(II): Structure, anticancer activity and anticancer mechanism.

In an effort to better understand the biological efficacy of the tridentate aroyl hydrazone Cu(II) complexes, three Cu(II) complexes of acetylpyridine benzoyl hydrazone (HL), [Cu(L)(NO3) (H2O)]·H2O (C1), [Cu(L)2] (C2) and [Cu(L)(HL)]·(NO3)(Sas) (C3) (Sas=salicylic acid) were synthesized and characterized. X-ray crystal structures and infrared (IR) spectra of the complexes reveal that the L(-) ligand of C1 and C2 are predominantly in the enolate resonance form, while one L(-) ligand in C3 is represented enolate resonance form and the other HL ligand exhibits keto resonance form. All Cu(II) complexes showed significantly more anticancer activity than the ligand alone. Interestingly, the Cu complexes where the ligand/metal ratio was 1:1 (C1) rather than 2:1 (C2 and C3) had higher antitumor efficacy. Moreover, the 1:1 Cu/ligand complex, C1, promotes A549 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.

Interaction of a copper (II) complex containing an artificial sweetener (aspartame) with calf thymus DNA.

A copper (II) complex containing aspartame (APM) as ligand, Cu(APM)2Cl2⋅2H2O, was synthesized and characterized. In vitro binding interaction of this complex with native calf thymus DNA (CT-DNA) was studied at physiological pH. The interaction was studied using different methods: spectrophotometric, spectrofluorometric, competition experiment, circular dichroism (CD) and viscosimetric techniques. Hyperchromicity was observed in UV absorption band of Cu(APM)2Cl2⋅2H2O. A strong fluorescence quenching reaction of DNA to Cu(APM)2Cl2⋅2H2O was observed and the binding constants (Kf) and corresponding numbers of binding sites (n) were calculated at different temperatures. Thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS) were calculated to be+89.3 kJ mol(-1) and+379.3 J mol(-1) K(-1) according to Van't Hoff equation which indicated that reaction is predominantly entropically driven. Experimental results from spectroscopic methods were comparable and further supported by viscosity measurements. We suggest that Cu(APM)2Cl2⋅2H2O interacts with calf thymus DNA via a groove interaction mode with an intrinsic binding constant of 8×10+4 M(-1). Binding of this copper complex to DNA was found to be stronger compared to aspartame which was studied recently.

Interactions of curcumin and its derivatives with nucleic acids and their implications.

Curcumin (diferuloylmethane) is a yellow polyphenol found in the rhizome of the annual herb turmeric (Curcuma longa) belonging to the family Zingiberaceae. Its interaction with a huge number of molecular targets like cytokines, growth factors, transcription factors, receptors, pro-inflammatory enzymes, protein kinases and adhesion molecules has been studied extensively. Interaction of curcumin with nucleic acids has been the focus of extensive research in recent years. Curcumin is observed to be genotoxic and antigenotoxic agent in time and concentration dependent manner. Curcumin and its derivatives either alone or as metal complexes have been reported to bind directly to DNA. The interactions are mainly as DNA minor groove binding or as DNA intercalating agents. The similarity in the shape of curcumin to DNA minor groove binding drugs is the motivation for exploring its binding to DNA minor grooves. Thus curcumin is a "double edged sword": having therapeutic potential as a minor groove binder but at the same time it may cause DNA damage in the cell at high concentration. The purpose of this review is to summarize the current information related to interaction of curcumin metal complexes and its derivatives with nucleic acids and the implication such interaction can have on therapeutics.