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The binding strengths of 1 and 2 were quantified from the values of intrinsic binding constant K b , determined by using Wolfe—Shimer equation The K b values were found to be 4. We carried out competitive binding studies by using ethidium bromide EthBr.


This assay differentiates between intercalator and non-intercalator 50 , Binding of EthBr with DNA in a stoichiometric ratio and then treating it with the tested molecule give rise to a change in fluorescence intensity. A significant decrease in emission intensity of DNA-EthBr suggests a displacement of EthBr molecule, which is the characteristic feature of an intercalator. The spectra clearly reveal intercalating ability of both 1 and 2 , by depleting EthBr from the bound EthBr-DNA and quenching the fluorescence intensity significantly.

Despite the fact that our copper I complexes do not have a perfect planar geometry, the aromatic rings of the phosphine moiety seem to play a significant role in the intercalation. In fact, the extent of quenching is quite substantial. However, non-intercalative interactions cannot be ruled out completely. Arrows show the emission intensity changes upon increasing the concentration of the complexes. The K q values obtained for complexes 1 and 2 are 8. Moreover, the apparent binding constants K app were calculated using the Eqn. The values of K app were found to be These findings are in agreement with the results and conclusions of the absorption spectral studies.

Since circular dichroism CD is a technique highly sensitive to changes in the conformation of the chiral structure of DNA 52 , 55 , it can be used to study the subtle variations upon its interaction with small molecules 56 , 57 , 58 , Intercalation enhances the intensity of both positive and negative bands, whereas groove binding and electrostatic interactions of complexes cause less or no perturbation on the base stacking and helicity bands. The spectrum of CT-DNA with complex 2 displayed a slight change in the conformation, which can be attributed to groove binding affinity along with electrostatic interactions Fig.

Therefore, the complex 1 is a better potential candidate to penetrate into the helical structure of the DNA, leading to a significant perturbation in the DNA structure Fig. However, the extent of intercalation is not very great, as still the conical B-form of the DNA is maintained, and thus a partial intercalative mode of action of 1 with DNA can be proposed.


The changes observed in the electrophoretic mobility pattern of pBR DNA, as a result of interactions with 1 , are quite evident. The appearance of new bands is attributed to DNA-complex interaction. In such type of complexes, coordinative type of bonding between the metal centre and DNA is less likely because of the favorable Cu I soft acid and soft donor ligand viz, -P and —S, and this coordination requires binding with N-donor hard donor ligand This band can be marked as the complex-DNA adduct formation, which has increased the molecular weight, and the adduct is unable to take part in electrophoretic mobility as compared to the control.

However, the mobility pattern revealed the concentration-dependent cleavage activity of the complex. To probe into the potential mechanism, we investigated the effect of reactive oxygen species ROS on the cleavage pattern of pBR DNA, upon interaction with complex 1 see Fig.

Thus, hydrolytic as well as oxidative mechanistic pathways can play a significant role in the cleavage pattern. The pattern exhibited higher affinity towards the minor grooves of DNA, as in this case the cleavage is significantly inhibited lanes 1 and 3 , whereas in the presence of the major groove binder the cleavage is not entirely inhibited lane 2 Fig.

The docked model Fig. Molecular docked model of i complex 1 and ii complex 2, in the a cavity of minor groove of DNA b binding site interactions with hydrogen bonding donor purple and acceptor green surface of minor groove residues. In order to determine the mechanistic basis for the inhibitory action and to obtain accurate binding mode of the hits on Topo—I, the complexes 1 and 2 were studied.

The resulting docked models exhibited a dual mode of binding on Topo—I due to conformation changes viz, structural flexibility of the interacting scorpionate moiety as well as anionic copper I coordinates chlorine atom. The carboxylic hydrogen atom of the complex 1 was H—bonded to Leu , which is considered an essential amino acid that interacts with the ligand in the DNA—Topo—I active site, whereas aromatic rings facing perpendicularly to the plane of base pairs which strongly block the rewinding step of the phosphoester.

Furthermore, DNA-intercalating forces were much more important than hydrogen bonding of the ligand to the surrounding amino acid residues of the protein, or to the base pairs. This result suggests that blocking the religation of the G11 hydroxyl group could be the main design point for novel Topo—I inhibitors. The docking models showed that complexes 1 and 2 were approaching the middle of ATP-binding pocket and stabilized by strong hydrophobic interactions with His, Pro, Val, Arg98, Leu and Met, Trp, and Ala for 1 and 2 , respectively Fig.

These multiple interactions between complexes and the residues in the ATPase domain and the magnesium ion suggest that the metal complexes can form a strong binding interaction with Topo II, preventing the entry of ATP. The complexes inhibited the growth of the liver cancer cells in a dose-dependent manner.


The IC 50 values are given in Table 5. The complex 1 showed effective cytotoxic activity against the liver cancer cell compared to the standard drug, Cisplatin. These cytological changes indicate that the cells were committed to a specific mode of cell death, either apoptosis or necrosis. A Hoechst staining of the complex 1 -induced apoptosis of HepG2 cells.

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To confirm the mode of cell death, we adopted acridine orange and ethidium bromide AO and EB staining. Observation of AO-EB stained cells in a fluorescent microscope revealed apoptosis greatly, but also necrosis to a certain extent, from the perspective of fluorescence emission. The results suggested that treatment with the complex 1 caused death of HepG2 cells through mostly apoptosis. However, the intercalative mode of interaction was also not completely ruled out.

We analyzed the electrophoretic pattern of pBR DNA upon interaction with 1, which gives concentration dependent cleavage pattern. The mechanistic study of DNA cleavage with complex 1 is suggestive of hydrolytic as well as oxidative pathways. Also, complex 1 exhibited preferential selectivity towards minor groove of the DNA.

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Then molecular modeling studies were carried out to justify our hypothesis of DNA binding affinity of the complex 1 , which corroborated well with above experimental findings. Complex 1 was tested against HepG2 human hepatocarcinoma cell line for anticancer activity. Further studies are required to strongly recommend the preclinical study of complex 1 as a cancer chemotherapeutic. Molar conductance was measured at room temperature on a Eutech CON conductivity bridge.

Solutions for electrospray ionization mass spectrometry ESI-MS were prepared using reagent-grade methanol and the obtained data masses and intensities were compared with those calculated by using the IsoPro isotopic abundance simulator, version 2. Emission spectra were determined with a Hitachi F fluorescence spectrophotometer.

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The optimized structures were further recalculated using def2—TZVP basis set for all atoms. The molecular docking studies have been performed by using Hex 8. All rotatable bonds within the ligand were allowed to rotate freely, and receptor was considered rigid. Visualization of minimum energy favorable docked poses has been performed using Discovery Studio 4. DNA binding experiments that included spectral absorption studies, and fluorescence, conformed to the standard methods 50 , 54 , 81 and practices previously adopted by our laboratory 82 , Standard error limits were estimated using all data points.

Machine plus cuvette baselines were subtracted, and the resultant spectra zeroed outside the absorption bands. In vitro anticancer experiments were carried out by standard protocol with slight modification as reported by us A solution containing CuCl 0.

The Chelate Effect Makes Complexes More Stable

Then the ligand L A 0. The resulting solution was kept for slow evaporation. Yield: 0. Found: C, Then the ligand L B 0. Cisplatin was used as the reference drug, and DMSO was used as the solvent control.

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A miniaturized viability assay using 3- 4,5-di-methyithiazolyl -2,5-diphenyl-2H-tetrazolium bromide MTT was carried out according to the method described by Mosman Data were collected for triplicates and used to calculate the respective means. The percentage inhibition was calculated from this data using the formula:.

The cells were trypsinized and pelleted and then suspended in PBS. At random, cells were observed in the fluorescent microscope at x magnification and the percentage of cells reflecting pathological changes was calculated. The percentage of cells reflecting pathological changes was calculated. How to cite this article: Khan, R. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Chapter 1. ISBN Siegel, R. Cancer Statistics, CA Cancer J. Clinicians , 66 , 7—30 Rosenberg, B. Platinum compounds: a new class of potent antitumour agents. Nature , , — Platinum complexes for the treatment of cancer. Galanski, M. Recent developments in the field of tumor-inhibiting metal complexes Curr. Noble metal complexes in cancer chemotherapy. Hill, J.

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Scorpionates II: Chelating Borate Ligands

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