Phenyl carbohydrazone conjugated 2-oxoindoline as a new scaffold that augments the DNA and BSA binding affinity and anti-proliferative activity of a 1,10-phenanthroline based copper(II) complex

A new type of copper(II) complex, CuL(phen)(2)](NO3) (CuIP), where L ((E)-N'-(2-oxoindolin-3-ylidene) benzohydrazide) is a N donor ligand and phen is the N, N-donor heterocyclic 1,10-phenanthroline, has been synthesized. The phenyl carbohydrazone conjugated isatin-based ligand L and CuIP were characterized by elemental analysis, infrared, UV-Vis, H-1 and C-13 NMR and ESI-mass spectral data, as well as single-crystal X-ray diffraction. The interaction of calf thymus DNA (CT DNA) with L and CuIP has been investigated by absorption, fluorescence and viscosity titration methods. The complex CuIP displays better binding affinity than the ligand L. The observed DNA binding constant (K-b = 4.15(+/- 0.18) x 10(5) M-1) and binding site size (s = 0.19), viscosity data together with molecular docking studies of CuIP suggest groove binding and/or a partial intercalative mode of binding to CT DNA. In addition, CuIP shows good binding propensity to the bovine serum albumin (BSA) protein, giving a K-BSA value of 1.25(+/- 0.24) x 10(6) M-1. In addition, the docking studies on DNA and human serum albumin (HSA) CuIP interactions are consistent with the consequence of binding experiments. The in vitro anti-proliferative study establishes the anticancer potency of the CuIP against the human cervical (HeLa) and breast (MCF7) cancer cells; noncancer breast epithelial (MCF10a) cells have also been investigated. CuIP shows better cytotoxicity and sensitivity towards cancer cells over noncancer ones than L under identical conditions, with the appearance of apoptotic bodies. (C) 2014 Elsevier B.V. All rights reserved.

Seleno-Nucleobases and Their Water-Soluble Ruthenium-Arene Half-Sandwich Complexes: Chemistry and Biological Activity

Half-sandwich organometallic ruthenium complexes of seleno-nucleobases, 3 and 4, were synthesized and characterized. The structures of both complexes were determined by X-ray crystallography and are the first crystal structures of ruthenium complexes with seleno-nucleobases. Interestingly, 3 self-assembles aided by adventitious water in DMF to give a tetranuclear square 3a center dot 6H(2)O. Complex 4 is active against Jurkat and Molt-4 cell lines but inactive against the K562 cell line, whereas 3 is completely inactive against all three cell lines. The free ligand 6-selenopurine (1) and 6-selenoguanine (2) are highly active against these cell lines. Compound 2, like its thio analogue, is unstable under UVA light, whereas 4 is stable under similar conditions, which suggests that the ruthenium complex could reduce problems associated with the instability of the free ligand, 2, under irradiation.

Direct regulation of topoisomerase activity by a nucleoid-associated protein

The topological homeostasis of bacterial chromosomes is maintained by the balance between compaction and the topological organization of genomes. Two classes of proteins play major roles in chromosome organization: the nucleoid-associated proteins (NAPs) and topoisomerases. The NAPs bind DNA to compact the chromosome, whereas topoisomerases catalytically remove or introduce supercoils into the genome. We demonstrate that HU, a major NAP of Mycobacterium tuberculosis specifically stimulates the DNA relaxation ability of mycobacterial topoisomerase I (TopoI) at lower concentrations but interferes at higher concentrations. A direct physical interaction between M. tuberculosis HU (MtHU) and TopoI is necessary for enhancing enzyme activity both in vitro and in vivo. The interaction is between the amino terminal domain of MtHU and the carboxyl terminal domain of TopoI. Binding of MtHU did not affect the two catalytic trans-esterification steps but enhanced the DNA strand passage, requisite for the completion of DNA relaxation, a new mechanism for the regulation of topoisomerase activity. An interaction-deficient mutant of MtHU was compromised in enhancing the strand passage activity. The species-specific physical and functional cooperation between MtHU and TopoI may be the key to achieve the DNA relaxation levels needed to maintain the optimal superhelical density of mycobacterial genomes.

Antioxidant activity and electrochemical elucidation of the enigmatic redox behavior of curcumin and its structurally modified analogues

Here, we report studies on the antioxidant activity and redox behavior of curcumin and its structurally modified synthetic analogues. We have synthesized a number of analogues of curcumin which abrogate its keto-enol tautomerism or substitute the methylene group at the centre of its heptadione moiety implicated in the hydride transfer and studied their redox property. From cyclic voltammetric studies, it is demonstrated that H-atom transfer from CH2 group at the center of the heptadione link also plays an important role in the antioxidant properties of curcumin along with that of its phenolic -OH group. In addition, we also show that the conversion of 1, 3-dicarbonyl moiety of curcumin to an isosteric heterocycle as in pyrazole curcumin, which decreases its rotational freedom, leads to an improvement of its redox properties as well as its antioxidant activity. (C) 2014 Elsevier Ltd. All rights reserved.

Structure-specific nuclease activity of RAGs is modulated by sequence, length and phase position of flanking double-stranded DNA

RAGs (recombination activating genes) are responsible for the generation of antigen receptor diversity through the process of combinatorial joining of different V (variable), D (diversity) and J (joining) gene segments. In addition to its physiological property, wherein RAG functions as a sequence-specific nuclease, it can also act as a structure-specific nuclease leading to genomic instability and cancer. In the present study, we investigate the factors that regulate RAG cleavage on non-B DNA structures. We find that RAG binding and cleavage on heteroduplex DNA is dependent on the length of the double-stranded flanking region. Besides, the immediate flanking double-stranded region regulates RAG activity in a sequence-dependent manner. Interestingly, the cleavage efficiency of RAGs at the heteroduplex region is influenced by the phasing of DNA. Thus, our results suggest that sequence, length and phase positions of the DNA can affect the efficiency of RAG cleavage when it acts as a structure-specific nuclease. These findings provide novel insights on the regulation of the pathological functions of RAGs.