Abstract
Ruthenium complexes have proved to exhibit antineoplastic activity, related to the interaction of the metal ion with DNA. In this context, synthetic and theoretical studies on ruthenium binding modes of thymine acetate (THAc) have been focused to shed light on the structure-activity relationship. This report deals with the reaction between dihydride ruthenium mer-[Ru(H)2(CO)(PPh3)3], 1 and the thymine acetic acid (THAcOH) selected as model for nucleobase derivatives. The reaction in refluxing toluene between 1 and THAcOH excess, by H2 release affords the double coordinating species κ1-(O)THAc-, κ2-(O,O)THAc-[Ru(CO)(PPh3)2], 2. The X-ray crystal structure confirms a simultaneous monohapto, dihapto- THAc coordination in a reciprocal facial disposition. Stepwise additions of THAcOH allowed to intercept the monohapto mer-κ1(O)THAc-Ru(CO)H(PPh3)3] 3 and dihapto trans(P,P)-κ2(O,O)THAc-[Ru(CO)H(PPh3)2] 4 species. Nuclear magnetic resonance (NMR) studies, associated with DFT (Density Function Theory)-calculations energies and analogous reactions with acetic acid, supported the proposed reaction path. As evidenced by the crystal supramolecular hydrogen-binding packing and 1H NMR spectra, metal coordination seems to play a pivotal role in stabilizing the minor [(N=C(OH)] lactim tautomers, which may promote mismatching to DNA nucleobase pairs as a clue for its anticancer activity.
Highlights
A plethora of novel developments on ruthenium complexes exhibited a remarkable efficiency as potential metal-drugs in anticancer treatments together with a consistent reduction of the related toxic issues exhibited by the former Pt-agents
A useful approach to shed some light on the mechanism related to biological action effectiveness [24] is to study the coordination modes of a metal-anchored thymine acetic acid (THAcOH), proposed here as ligand to design potential bioactive ruthenium complexes
On a PerkinElmer Spectrum 2000 FT-IR (Fourier transform infrared) spectrophotometer (Waltham, MA, USA), electrospray ionization mass spectrometry (ESI MS) spectra were recorded on a Waters Micromass ZQ 4000 (Milford, MA, USA), with samples dissolved in CH3 OH
Summary
A plethora of novel developments on ruthenium complexes exhibited a remarkable efficiency as potential metal-drugs in anticancer treatments together with a consistent reduction of the related toxic issues exhibited by the former Pt-agents. It is of fundamental importance to disclose more evidence on the structure–effect relationship In this respect, great efforts have been made in ruthenium novel drugs [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16] exploration, focused on the interaction modes towards DNA nucleic bases [17,18,19,20,21,22,23]. Evaluation of the 1 H nuclear magnetic resonance (NMR) intermolecular H-bonding [25] signals has been suggested by the help of DFT-calculated energies, through simulation of the interactions of two THAc- anions, selected as model
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