Saurabh Das

Electrochemical Reduction of Quinones in Different Media: A Review

The electron transfer reactions involving quinones, hydroquinones, and catechols are very important in many areas of chemistry, especially in biological systems. The therapeutic efficiency as well as toxicity of anthracycline anticancer drugs, a class of anthraquinones, is governed by their electrochemical properties. Other quinones serve as important functional moiety in various biological systems like electron-proton carriers in the respiratory chain and their involvement in photosynthetic electron flow systems. The present paper summarizes literatures on the reduction of quinones in different solvents under various conditions using different electrochemical methods. The influence of different reaction conditions including pH of the media, nature of supporting electrolytes, nature of other additives, intramolecular or intermolecular hydrogen bonding, ion pair formation, polarity of the solvents, stabilization of the semiquinone and quinone dianion, catalytic property, and adsorption at the electrode surface, are discussed and relationships between reaction conditions and products formed have been presented.

Studies on the formation of a complex of Cu(II) with sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate – An analogue of the core unit of anthracycline anticancer drugs and its interaction with calf thymus DNA

Copper(II) forms a complex with sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (sodium quinizarin-2-sulphonate, NaQSH(2)), an analogue of the core unit of anthracycline antibiotics used in the treatment of cancer. The 1:2 metal-ligand complex is formed in aqueous solution at neutral and acidic pH while in alkaline pH both 1:1 and 1:2 species are formed. The effective stability constant of the 1:2 metal-ligand complex is 9.64x10(16) while that of the 1:1 metal-ligand complex is 9.4x10(9). The 1:2 complex Cu(NaQSH)(2)(H(2)O)(2) was synthesized and characterized by different techniques in solid state and in solution. The complex Cu(NaQSH)(2)(H(2)O)(2) interacts with calf thymus DNA which was studied by fluorescence spectroscopy. The binding constant and site size for the interaction with DNA were determined.

X-ray crystal structure of a Cu(II) complex with the antiparasitic drug tinidazole, interaction with calf thymus DNA and evidence for antibacterial activity

Interaction of metal ions with biologically active molecules like 5-nitroimidazoles modulates their electronic environment and therefore influences their biological function. In the present work, an antiparasitic drug tinidazole (tnz) was selected and a Cu(II) complex of tnz [Cu2(OAc)4(tnz)2] was prepared. A dinuclear paddle-wheel [Cu2(OAc)4(tnz)2] was obtained by single-crystal XRD and further characterized by spectroscopic techniques and cyclic voltammetry. To understand the biological implications of complex formation, interaction of tnz and its complex was studied with calf thymus DNA, bacterial and fungal cell lines. Results of calf thymus DNA interaction using cyclic voltammetry indicate the overall binding constant (K*) of Cu2(OAc)4(tnz)2 [(59 ± 6) × 104 M−1] is ~17 times greater than that of tnz [(3.3 ± 0.4) × 104 M−1]. Minimum inhibitory concentration values suggest that [Cu2(OAc)4(tnz)2] possesses better antibacterial activity than tnz on both bacterial strains, while the activity on a fungal strain was comparable. Tinidazole, a 5-nitroimidazole is active on protozoan and bacterial infections. This study made an attempt to see if a Cu(II) complex of tinidazole had comparable efficacy on chosen bacteria and fungi. The prepared complex was characterized by XRD, spectroscopy, elemental analysis cyclic voltammetry. DNA interaction was studied using cyclic voltammetry and fitted by non-linear analysis.

Synthesis, crystal structure, DNA interaction and in vitro anticancer activity of a Cu(II) complex of purpurin: dual poison for human DNA topoisomerase I and II

Although generation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for anti-tumor activity, they make these drugs cardiotoxic. Metal–anthracyclines that generate relatively fewer ROS are however, effective antitumor agents. Purpurin (LH3), a hydroxy-9,10-anthraquinone, closely resembles doxorubicin, an established anthracycline drug. This molecule was chosen to study the extent to which simpler analogues are effective. A Cu(II) complex of LH3 [Cu(II)–(LH2)2] was synthesized to mimic the metal–anthracycline complexes. The crystal structure of [Cu(II)–(LH2)2] was determined by Rietveld refinement of PXRD data using an appropriate structural model developed on the basis of spectroscopic data. This is the first report on the crystal structure of any hydroxy-9,10-anthraquinone with a 3d-transition metal ion. The bond lengths and bond angles obtained by structural refinement corroborate those calculated by the DFT method. DNA binding of the complex was slightly better than purpurin. However, more importantly, unlike purpurin, binding constant values did not decrease with increasing pH of the medium. DNA relaxation assays show Cu(II)–(LH2)2 as a novel potent dual inhibitor of human DNA topoisomerase I and topoisomerase II enzymes. Cu(II)–(LH2)2 stabilizes covalent topoisomerase–DNA adducts both in vitro and within cancer cells. The cleavage assay keeps the complex well ahead of LH3 with regard to efficacy. These results paralleled those of cell growth inhibition and showed that the complex was more effective in killing ALL MOLT-4 cells than LH3, suggesting it targets topoisomerase enzymes within cells. The NADH dehydrogenase assay revealed further that the generation of superoxide was less in the case of the complex as compared to LH3.

Enhancement of anti-leukemic potential of 2-hydroxyphenyl-azo-2′-naphthol (HPAN) on MOLT-4 cells through conjugation with Cu(II)

A Cu(II) complex of 2-hydroxyphenyl-azo-2′-naphthol (HPAN) having the formula CuII(HPAN)2 was characterized by different techniques. When HPAN and CuII(HPAN)2 were incubated for 24 hours with human T-acute lymphoblastic leukemia (MOLT-4) cells, almost no activity was observed for HPAN while the complex was active. When incubated for 48 hours, HPAN showed cell death of ∼35% at a concentration of 40 μM while CuII(HPAN)2 was only slightly better than when incubated for 24 hours. Therefore, irrespective of incubation time, the anti-proliferative activity due to CuII(HPAN)2 was similar. However, increase in incubation time did show increased activity for HPAN. Anti-leukemic potential was confirmed by microscopic analysis of cell viability by trypan blue stain and MTT assay. The BrdU assay further confirmed proliferative effects of aqueous Cu(II)/HPAN and anti-proliferative effects of Cu(II)(HPAN)2. Propidium iodide staining of Cu(II)(HPAN)2-treated MOLT-4 cells confirmed apoptosis. Since amines formed as a consequence of reduction of the azo bond are reported to be cytotoxic, we performed an enzyme assay to understand the relative reduction of the azo bond in both compounds. Results suggest reduction of the azo bond was slightly higher for HPAN. DNA binding of CuII(HPAN)2 using fluorescence spectroscopy was compared with that of HPAN to determine the propensity of biological activity. The results being similar, binding of the compounds with DNA and the ease of reduction of the azo bond were not able to explain why CuII(HPAN)2 was better in preventing cell proliferation. The high anti-proliferative activity of CuII(HPAN)2 was attributed to increased cellular uptake. We designed experiments to support this hypothesis using independent approaches. In one, Cu(II) was identified in cell lysates using ferrocyanide, while, in another, CuII(HPAN)2 was detected using flow cytometry. We chose Cu(II) as the metal ion for this work because of its recognized involvement in cancer. Being essential for angiogenesis, it is found in increased levels in cancer cells. Interaction of Cu(II)(aq) with MOLT-4 cells confirmed this as a part of this study also. Hence, our objective was to see if molecules like HPAN that bind Cu(II) could lead to its role reversal, i.e. from supporting the growth of cancer cells to be able to destroy them as CuII(HPAN)2.

A comparative study on the interaction with calf thymus DNA of a Ni(II) complex of the anticancer drug adriamycin and a Ni(II) complex of sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate

The anthracycline drug adriamycin and its metal complexes are efficient in treating several forms of human cancers with recognized antineoplastic activity attributed to strong interactions with DNA within the target cells. The hydroxy-9,10-anthraquinone unit present in the molecule controls and regulates drug action. Metal ions when linked to adriamycin help to reduce the generation of radicals responsible for toxic side effects. A complex of adriamycin with Ni(II) was prepared and its physicochemical characteristics and DNA-binding ability were compared to a Ni(II) complex of sodium-1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (NaLH2), an analog of adriamycin. Interactions with calf thymus DNA of both complexes were studied by UV-Vis and fluorescence spectroscopy. Binding parameters determined for both complexes agree with each other. Binding of the Ni(II)-adriamycin complex to DNA was five to eight times stronger than for the Ni(II) complex of the hydroxy-9,10-anthraquinone analog, Na2[Ni(NaLH)2Cl2] · 2H2O, i.e., Ni(NaLH)2. The difference in binding was attributed to the presence of sugar units in adriamycin and to its absence in NaLH2. Although the Ni(II) complex of the hydroxy-9,10-anthraquinone analog of adriamycin [Ni(NaLH)2] was slightly weaker in binding DNA than the drug and its Ni(II) complex, a much lower cost of the former justifies its consideration as a substitute for the anthracycline drugs that are now in use.

A complex of Co(II) with 2-hydroxyphenyl-azo-2'-naphthol (HPAN) is far less cytotoxic than the parent compound on A549-lung carcinoma and peripheral blood mononuclear cells: Reasons for reduction in cytotoxicity.

Cytotoxic studies using an azo compound HPAN and its Co(II) complex were carried out on non-small lung epithelium carcinoma (A549) cells and peripheral blood mononuclear (PBM) cells. The results obtained suggest that the Co(II) complex is much less toxic toward both cell lines and the decreased toxicity due to the complex was more pronounced with carcinoma A549 cells. An attempt was made to correlate the findings related to cytotoxicity with the interaction of the compounds with DNA using calf thymus DNA as the target. The study was able to conclude that the complex was a relatively weak binder to calf thymus DNA. This information was used to explain the interaction of azo compounds with DNA in peripheral blood mononuclear cells and A549 lung carcinoma cells. It was concluded that the Co(II) complex interacts with DNA to a much lesser extent than HPAN alone. Cyclic voltammetry experiments carried out with HPAN and the Co(II) complex further showed that the presence of the metal ion in the complex prevents reduction of the azo group to such species that are responsible for inducing cytotoxicity. The overall finding was that complex formation with azo compounds might serve as a possible route to curb their toxicities.

Interaction of Calf Thymus DNA with the Ni(II) Complex of Sodium 1,4-Dihydroxy-9,10-Anthraquinone-2-Sulphonate: A Novel Method of Analysis Using Cyclic Voltammetry

Hydroxy-9,10-anthraquinones are cheaper alternatives to anthracycline drugs. They closely resemble anthracycline drugs both from a structural and functional viewpoint. Electrochemical behavior of the Ni(II) complex (Na2[Ni(NaLH)2Cl2]⋅2H2O) of sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (NaLH2), analogue of the core unit of anthracycline anticancer drugs, was studied at physiological pH using cyclic voltammetry. The Ni(II) complex of sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate undergoes diffusion-controlled one-electron reduction that enables performing an electrochemical study on the interaction of the complex with calf thymus DNA. The complex was titrated with increasing concentrations of DNA, and the reduction peak for the unbound complex helped in evaluating binding parameters. Analysis of binding data using nonlinear curve fit in a cyclic voltammetry experiment is the first such attempt. The paper evaluates site size of interaction that also serves as a means to determine stoichiometry of complex formation, between a metal ion and ligand from a DNA interaction study, probably a first of its kind.

The Water Fraction of Calendula officinalis Hydroethanol Extract Stimulates In Vitro and In Vivo Proliferation of Dermal Fibroblasts in Wound Healing.

The active fraction and/or compounds of Calendula officinalis responsible for wound healing are not known yet. In this work we studied the molecular target of C. officinalis hydroethanol extract (CEE) and its active fraction (water fraction of hydroethanol extract, WCEE) on primary human dermal fibroblasts (HDF). In vivo, CEE or WCEE were topically applied on excisional wounds of BALB/c mice and the rate of wound contraction and immunohistological studies were carried out. We found that CEE and only its WCEE significantly stimulated the proliferation as well as the migration of HDF cells. Also they up‐regulate the expression of connective tissue growth factor (CTGF) and α‐smooth muscle actin (α‐SMA) in vitro. In vivo, CEE or WCEE treated mice groups showed faster wound healing and increased expression of CTGF and α‐SMA compared to placebo control group. The increased expression of both the proteins during granulation phase of wound repair demonstrated the potential role of C. officinalis in wound healing. In addition, HPLC‐ESI MS analysis of the active water fraction revealed the presence of two major compounds, rutin and quercetin‐3‐O‐glucoside. Thus, our results showed that C. officinalis potentiated wound healing by stimulating the expression of CTGF and α‐SMA and further we identified active compounds. Copyright

Acetylation of 1,2,5,8-tetrahydroxy-9,10-anthraquinone Improves Binding to DNA and Shows Enhanced Superoxide Formation that Explains Better Cytotoxicity on JURKAT T Lymphocyte Cells

Background : Hydroxy-9,10-anthraquinones form the core unit of anthracycline anticancer drugs and are close structural analogues to these drugs. Although they show close resemblance to anthracyclines in physicochemical characteristics and electrochemical behavior their biophysical interactions are somewhat weaker than anthracyclines which is a disadvantage. One reason is the formation of anionic species by hydroxy-9,10-anthraquinones. Hence if formation of anionic species is prevented there could be a possibility hydroxy-9,10-anthraquinones would bind DNA better. Procedure : For this 1, 2, 5, 8-tetrahydroxy-9,10-anthraquinone (THAQ) was acetylated to obtain a tetra-acetylated derivative (THAQ-ace) whose interaction with calf thymus DNA was studied using UV-Vis spectroscopy at different pH. Results : Binding constant values for THAQ-ace (~10 5 ) were higher than THAQ at different pH. Increase in binding constant was attributed to anionic species not formed for THAQ-ace at physiological pH. Hence, unlike THAQ, binding constant values for THAQ-ace interacting with calf thymus DNA did not show variation with pH. In fact, it remained more or less constant. Increase in size of the acetylated form (THAQ-ace) compared to THAQ had a negative influence on binding. THAQ-ace showed enhanced superoxide formation. Both DNA binding and superoxide formation were responsible for a significant improvement in anticancer activity for THAQ-ace compared to THAQ on Jurkat T lymphocyte cells . Conclusion : Binding constant values for THAQ-ace binding to DNA were close to that reported for some standard anthracyclines. Hence, suitable modification of the less costly hydroxy-9,10-anthraquinones could provide alternatives to anthracyclines in cancer chemotherapy.