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A monomeric complex of ZnII with ornidazole [Zn(Onz)2Cl2] decreases formation of the nitro-radical anion (R–NO2˙−), and this is realized by recording it in an enzyme assay using xanthine oxidase, which is a model nitro-reductase. Although the formation of R–NO2˙− is essential for drug action, as it is also associated with neurotoxic side effects, it is imperative to control its generation in order to avoid excess presence. With a decrease in R–NO2˙−, while the neurotoxic side effects should decrease, it can be expected that a compromise with regard to therapeutic efficacy will be seen since the complex will be less active in the free radical pathway. Since R–NO2˙− is crucial for the functioning of 5-nitroimidazoles, we attempted to find out if its biological activity is affected in any way in our effort to control its formation. For this purpose, Entamoeba histolytica (HM1:IMS Strain) was chosen as a biological target to realize the performance of the complex with respect to ornidazole (R–NO2). The experiments revealed that the complex not only compares well with ornidazole, but in fact, under longer exposure times, it also performs better than it. This efficacy of the complex was seen despite a decrease in R–NO2˙−, as identified by an enzyme assay, and this was probably due to certain attributes of the complex formation that are not known for ornidazole. These attributes outweigh any loss in efficacy in the free radical pathway following complex formation. This is certainly an advantage of complex formation and helps to improve the therapeutic index. This study has attempted to look at some of the possible reasons why the complex performs better than ornidazole. One reason is its ability to bind to DNA better than ornidazole does, and this can be understood by following the interaction of ornidazole and its Zn(II) complex with calf-thymus DNA using cyclic voltammetry. Therefore, this study showed that despite a decrease in R–NO2˙−, the complex does not compromise its efficacy, and this was examined using a biological target. In addition, the complex is likely to have less toxic side effects on the host of the disease-causing microbes.

A monomeric complex of Zn

Emodin, a hydroxy-9,10-anthraquinone, resembles anthracycline anticancer drugs at the core and possesses anticancer activities. A CuII complex of emodin [CuII(emod)2]2− was synthesized and its crystal structure was determined by Rietveld refinement of the PXRD data by using an appropriate structural model based on spectroscopy. This is the third report on the crystal structure of a hydroxy-9,10-anthraquinone with a 3d-transition metal ion. Since the formation of reactive oxygen species (ROS) by anthracycline-based anticancer drugs is important for antitumor activity and given the fact that the generation of ROS is responsible for cardiotoxic side effects, it is essential to be able to control their formation. Complex formation decreases ROS generation and could thereby lead to a decrease in cardiotoxic side effects. However, in an attempt to decrease complications, there is also the possibility of compromising the therapeutic efficacy. For this reason, the activities of emodin and its modified form [Cu(II) complex] were studied on the carcinoma cell lines HeLa and Hep G2 to see how they compared with each other in terms of performance. Studies were also performed on WI 38 lung fibroblast normal cells. The studies revealed that, in spite of the decreased ROS formation, followed by the DCFDA assay, the Cu(II) complex showed better activity on carcinoma cell lines. This suggests that the complex has other attributes that enable it to perform better than emodin. Consequently, one such attribute, namely DNA binding, was thoroughly investigated by varying the ionic strength and the temperature of the medium. It was found that the complex was able to bind DNA better than emodin, and, more importantly, since both generate a good amount of anionic species in solution under increased ionic strength of the medium, both bind DNA better; the increase in binding with increase in ionic strength being higher for the complex. The study suggests that with a substantial decrease in ROS generation by the complex, there are likely to be less toxic side effects, which is a key advantage of the complex, leading to an improvement in the therapeutic index. The complex showed almost no activity on WI 38 normal cells.

The formation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for their antitumor activity but they also make these drugs cardiotoxic. When complexed with metal ions there is a decrease in ROS formation and therefore in cardiotoxicity. Interestingly, in spite of producing fewer ROS, some of the complexes are effective antitumor agents, often better than the parent anthracycline. Purpurin (LH3), a hydroxy-9,10-anthraquinone, resembles doxorubicin at the core. An MnII complex of LH3 [MnII(LH2)2] was synthesized to see the extent to which the complex resembles metal–anthracyclines with regard to structure and function. The crystal structure was determined by Rietveld refinement of PXRD data using an appropriate structural model developed on the basis of spectroscopic information. This is only the second report on the crystal structure of a hydroxy-9,10-anthraquinone with a 3d-transition metal ion. Bond lengths and bond angles were obtained by structural refinement. The structure is supported by DFT calculations. DNA binding of the complex is slightly better than for purpurin but more importantly unlike purpurin, the binding constant values remained constant even with an increase in the pH of the medium. The NADH dehydrogenase assay and the DCFDA-ROS generation assay showed that generation of superoxide in the former and ROS in general in the latter were significantly less for the complex than for purpurin. Even with decreased ROS formation, the complex is able to maintain the biological activity of purpurin.