R a comparative analysis of caffeine, theophylline with the other structurally related compounds liketheobromine has not yet been shown to understand their variance in 125-65-5 web binding efficacy with DNA, as all of them are having vital cellular activities. Moreover, the current study deals the binding interaction of all these three methylxanthines with DNA in the presence of divalent metal ions and during helix-coil transition state holding some key rationales are explicitly explored in detail. As far as the importance of theobromine is concerned it has been shown that theobromine enhanced the antitumor activity of adriamycin with reduced toxicity [18,19]. It has also been reported that caffeine and theobromine inhibited the doxorubicin efflux from tumor cells and increased the tumoricidal activity with reduced side effect [8]. From our earlier reports it could be understood that since xanthine derivatives can interact with DNA, they can reduce the DNA-directed toxicity of certain intercalating dyes such as ethidium bromide, acridine orange and antitumor agents like cisplatin, novantrone, actinomycin D etc [16]. Moreover, co-administration of methylxanthines in cancer therapy used for the enhancement of anti-tumor agent’s activity and serving as candidates for radiosensitization are promising baselineMethylxanthines Binding with DNAFigure 1. The chemical PS 1145 web structure of naturally occurring methylxanthines. doi:10.1371/journal.pone.0050019.gfor developing methylxanthines as potential secondary enhancers for future clinical trial [20?3]. It is worthwhile to mention here that caffeine and theophylline decrease the replication 1480666 of the virus HIV-1 strain [24]. We have also demonstrated that methylxanthines can modulate the self-splicing activity of group I intron, showing both theophylline and theobromine relatively reduce the splicing activity of group I intron as compared to that of the control self-splicing reaction. However, caffeine, with structural difference 1676428 of a single methyl group at the N-7 position, was not effective, and thus forming the baseline for the development of splicing inhibitors with possible role of RNA as drug target [25] (Fig. 1). The rationales for studying the interaction of methylxanthines in the presence of divalent metal ions are mainly due to a fact that these divalent metal ions are being preferred for many enzymatic activities and also needed for many small molecule drugs and antibiotics for their effective biding to DNA or RNA or cellular proteins. The recent trends on the binding interaction of metal ions with cellular components by itself or together with other drug molecules bring out either beneficial or non-beneficial cellular effects. For instance higher DNA-acting efficacy is noticed for the DNA-binding anticancer agents such as Chromomycin A3 in the presence of divalent metal ions [26]. Divalent metal ions such as magnesium is the preferred divalent metal ion for efficient and specific cleavage reaction of I-BmoI endonucleases [27].The activity of “Core A” transporter protein depends on the binding of divalent metal ions where the interaction of magnesium ions to its interhelical loops is explored in detail [28]. On the other hand studying the binding interactions and the affinity of some of the non-beneficial divalent metal ions in the cellular system is highly helpful to identify their toxicities to vital cells. In this respect the divalent metal ions such as Pb2+ interact with the His-330 and His362 residues.R a comparative analysis of caffeine, theophylline with the other structurally related compounds liketheobromine has not yet been shown to understand their variance in binding efficacy with DNA, as all of them are having vital cellular activities. Moreover, the current study deals the binding interaction of all these three methylxanthines with DNA in the presence of divalent metal ions and during helix-coil transition state holding some key rationales are explicitly explored in detail. As far as the importance of theobromine is concerned it has been shown that theobromine enhanced the antitumor activity of adriamycin with reduced toxicity [18,19]. It has also been reported that caffeine and theobromine inhibited the doxorubicin efflux from tumor cells and increased the tumoricidal activity with reduced side effect [8]. From our earlier reports it could be understood that since xanthine derivatives can interact with DNA, they can reduce the DNA-directed toxicity of certain intercalating dyes such as ethidium bromide, acridine orange and antitumor agents like cisplatin, novantrone, actinomycin D etc [16]. Moreover, co-administration of methylxanthines in cancer therapy used for the enhancement of anti-tumor agent’s activity and serving as candidates for radiosensitization are promising baselineMethylxanthines Binding with DNAFigure 1. The chemical structure of naturally occurring methylxanthines. doi:10.1371/journal.pone.0050019.gfor developing methylxanthines as potential secondary enhancers for future clinical trial [20?3]. It is worthwhile to mention here that caffeine and theophylline decrease the replication 1480666 of the virus HIV-1 strain [24]. We have also demonstrated that methylxanthines can modulate the self-splicing activity of group I intron, showing both theophylline and theobromine relatively reduce the splicing activity of group I intron as compared to that of the control self-splicing reaction. However, caffeine, with structural difference 1676428 of a single methyl group at the N-7 position, was not effective, and thus forming the baseline for the development of splicing inhibitors with possible role of RNA as drug target [25] (Fig. 1). The rationales for studying the interaction of methylxanthines in the presence of divalent metal ions are mainly due to a fact that these divalent metal ions are being preferred for many enzymatic activities and also needed for many small molecule drugs and antibiotics for their effective biding to DNA or RNA or cellular proteins. The recent trends on the binding interaction of metal ions with cellular components by itself or together with other drug molecules bring out either beneficial or non-beneficial cellular effects. For instance higher DNA-acting efficacy is noticed for the DNA-binding anticancer agents such as Chromomycin A3 in the presence of divalent metal ions [26]. Divalent metal ions such as magnesium is the preferred divalent metal ion for efficient and specific cleavage reaction of I-BmoI endonucleases [27].The activity of “Core A” transporter protein depends on the binding of divalent metal ions where the interaction of magnesium ions to its interhelical loops is explored in detail [28]. On the other hand studying the binding interactions and the affinity of some of the non-beneficial divalent metal ions in the cellular system is highly helpful to identify their toxicities to vital cells. In this respect the divalent metal ions such as Pb2+ interact with the His-330 and His362 residues.
