Ramesh Chandra Santra

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 and characterization of 5-amino-2-((3-hydroxy-4-((3-hydroxyphenyl) phenyl) diazenyl) phenol and its Cu(II) complex – a strategy toward developing azo complexes for reduction of cytotoxicity

A major drawback of azo compounds is their associated toxicity, often carcinogenic, which is related to the reduction of the azo bond. This study intends to re-investigate this behavior by studying 5-amino-2-((3-hydroxy-4-((3-hydroxyphenyl) phenyl) diazenyl) phenol (AHPD), a compound containing two azo bonds. Interaction of AHPD and its dimeric Cu(II) complex with bacterial strains Escherichia coli and Staphylococcus aureus revealed the complex was less toxic. Reductive cleavage of the azo bond in AHPD and the complex followed using cytochrome c reductase (a model azo-reductase) as well as azo-reductase enzymes obtained from bacterial cell extracts. Degradation of the azo bond was less in the complex allowing us to correlate the observed cytotoxicity. Cyclic voltammetry on AHPD and the complex support observations of enzyme assay experiments. These were particularly useful in realizing the formation of amines as an outcome of the reductive cleavage of azo bonds in AHPD that could not be identified through an enzyme assay. Results suggest that complex formation of azo compounds could be a means to control the formation of amines responsible for cytotoxicity. Studies carried out on bacterial cells for mere simplicity bear significance for multicellular organisms and could be important for human beings involved with the preparation and utilization of azo dyes.

Synthesizing a CuII complex of tinidazole to tune the generation of the nitro radical anion in order to strike a balance between efficacy and toxic side effects

A monomeric complex of Cu(II) with tinidazole [Cu(tnz)2Cl2] was synthesized. The complex decreases the formation of the nitro-radical anion (NO2˙−), which was followed by an enzyme assay involving xanthine oxidase, a model nitro-reductase. It has a binding constant value with DNA comparable to that of tinidazole. In addition to the drug efficacy of the nitro radical anion, it also has neurotoxic side effects; so it is essential to control its formation to an optimum, sufficient for bringing about cytotoxic activity on disease causing microbes but avoiding excess that could make it neurotoxic. If this is achieved through modification of the 5-nitroimidazole moiety then too much NO2˙− would not be generated, implying that the chances of the drug causing any harm to the host due to toxic side effects could be reduced. However, with decreased NO2˙− formation, in an effort to decrease complications, a certain amount of therapeutic efficacy would be compromised. Therefore, the biological activity of tinidazole and its modified form, a monomeric complex, was investigated to see how the latter compares with tinidazole under comparable conditions. Studies revealed that, in spite of decreased NO2˙− formation, the complex showed similar activity to that of tinidazole on two bacterial strains and an amoeba strain, implying that it has other attributes, not known for 5-nitroimidazoles, that enable it to match the efficacy of tinidazole. The study suggests that there is a substantial decrease in NO2˙− due to the formation of the tinidazole complex, meaning that the toxic side effects are likely to be reduced which is an advantage as it would improve the therapeutic index.

Correction: The biological in vitro effect and selectivity shown by a CoII complex of 2-(2-hydroxyphenylazo)-indole-3′-acetic acid on three distinctly different cancer cells

A major intention of this study was to use the modified toxicity of the azo moiety in [2-(2-hydroxyphenylazo)-1H-indol-3-yl]-acetic acid (HPIA), achieved through complex formation with CoII on some cancer cell lines. This is important because the azo functional group has not been tried in cancer chemotherapy. Keeping in mind aspects of drug resistance of some of the common anticancer drugs, a serious problem and a major clinical challenge in cancer chemotherapy, it is essential that new molecules are identified with anticancer activity. Although cytotoxicity of azo compounds is established there are not many reports that utilize them in cancer treatment. Another important aspect is to prepare compounds having preferential activity on cancer cells over normal cells so that toxic side effects are a minimum. Enzyme assay on the reductive cleavage of the azo bond showed complex formation with CoII almost completely checked the generation of cytotoxic amines implying that the complex could be less cytotoxic which was actually observed in case of normal healthy cells. Even though the complex formed less cytotoxic amines and possessed an almost similar binding ability with DNA like that of HPIA surprisingly its activity on three cancer cell lines namely human colon carcinoma HCT116 cells, acute lymphoblastic leukemia MOLT-4 cells and MCF-7 breast cancer cells was much greater than HPIA. The difference in activity between HPIA and its CoII complex on cancer cells showed no correlation with DNA binding or amine formation like that observed for normal cells. The complex probably possesses multiple modes of action whereby it is able to inhibit one or more cellular processes or functioning of different enzymes involved in the cell cycle of cancer cells for which it was found more effective.

γ radiation-induced damage of nucleic acid bases, calf thymus DNA and DNA within MCF-7 breast cancer cells by [Cu2(OAc)4(tnz)2]: a potential radiosensitizer

A dimeric complex of Cu(II) with tinidazole characterized earlier was used to study radiosensitizing attributes. Studies reveal that the complex is better than tinidazole in sensitizing radiation-induced damage of nucleic acid bases uracil and thymine, radiation-induced double strand modification of calf thymus DNA and modification of DNA within MCF-7 breast cancer cells. The unique aspect of this study is that in spite of a substantial decrease in the generation of the nitro-radical anion (NO2˙−) following complex formation of tinidazole with Cu(II), no decrease was observed in the radiosensitizing attribute of nitroimidazoles. Rather the complex was clearly ahead of tinidazole with regard to radiosensitization. Hence, complex formation of important drug molecules are an advantage since it helps to target DNA better. This study serves as a good example where a common intermediate (NO2˙−) responsible for efficacy as well as toxic side effects can be suitably tuned in its generation using a modified form of 5-nitroimidazole (here tinidazole) to be able to strike the correct balance between efficacy and toxic side effects.