| Summary: | 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)<sub>2</sub>(CO)(PPh<sub>3</sub>)<sub>3</sub>], <b>1</b> and the thymine acetic acid (THAcOH) selected as model for nucleobase derivatives. The reaction in refluxing toluene between <b>1</b> and THAcOH excess, by H<sub>2</sub> release affords the double coordinating species κ<sup>1</sup>-(O)THAc-, κ<sup>2</sup>-(O,O)THAc-[Ru(CO)(PPh<sub>3</sub>)<sub>2</sub>], <b>2</b>. 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-κ<sup>1</sup>(O)THAc-Ru(CO)H(PPh<sub>3</sub>)<sub>3</sub>] <b>3</b> and dihapto <i>trans</i><sub>(P,P)</sub>-κ<sup>2</sup>(O,O)THAc-[Ru(CO)H(PPh<sub>3</sub>)<sub>2</sub>] <b>4</b> 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 <sup>1</sup>H 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.
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