Abstract
Lawsone itself exhibits interesting biological activities, and its complexation with a metal center can improve the potency. In this context a cytotoxic Ru-complex, [Ru(law)(dppb)(bipy)] (law = lawsone, dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2′-bipyridine), named as CBLAU, was prepared as reported. In this work, NMR binding-target studies were performed to bring to light the most accessible interaction sites of this Ru-complex toward Calf-Thymus DNA (CT-DNA, used as a model), in a similar approach used for other metallic complexes with anti-cancer activity, such as cisplatin and carboplatin. Advanced and robust NMR binding-target studies, among them Saturation Transfer Difference (STD)-NMR and longitudinal relaxometry (T1), were explored. The 1H and 31P -NMR data indicate that the structure of Ru-complex remains preserved in the presence of CT-DNA, and some linewidth broadening is also observed for all the signals, pointing out some interaction. Looking at the binding efficiency, the T1 values are highly influenced by the formation of the CBLAU-DNA adduct, decreasing from 11.4 s (without DNA) to 1.4 s (with DNA), where the difference is bigger for the lawsone protons. Besides, the STD-NMR titration experiments revealed a stronger interaction (KD = 5.9 mM) for CBLAU-DNA in comparison to non-complexed lawsone-DNA (KD = 34.0 mM). The epitope map, obtained by STD-NMR, shows that aromatic protons from the complexed lawsone exhibits higher saturation transfer, in comparison to other Ru-ligands (DPPB and bipy), suggesting the supramolecular contact with CT-DNA takes place by the lawsone face of the Ru-complex, possibly by a spatial π-π stacking involving π-bonds on nucleic acids segments of the DNA chain and the naphthoquinone group.
Highlights
Cancer is among the major public health problems worldwide and is responsible for millions of deaths, only in the United States (Siegel et al, 2019)
Despite the presence of these residues, they do not interfere in the interaction between CBLAU and Calf-thymus DNA (CT-DNA), as it will be shown in the following discussions
9.8 lawsone and bipyridine are mostly affected by the presence of CT-DNA and these findings indicate that these groups exhibit a shorter contact with CT-DNA surface
Summary
Cancer is among the major public health problems worldwide and is responsible for millions of deaths, only in the United States (Siegel et al, 2019). For the longitudinal relaxation time (T1) constant determination, was used the monoexponential fitting for the experimental obtained data, using for this purpose the software Topspin 3.5 pl.7 These experiments were recorded by using a Bruker standard pulse sequence with water supression (stddiffesgp.3), with a pseudo-2D setup through an intervaled acquisition of an on- and off-resonance experiment. After getting the ASTD and αSTD values, the curves ASTD vs. concentration were built up, linearized and fitted using a linear fit employing the MS Excel (2007) and plotted using the software Origin, version 8.0
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