Ruthenium–Thymine Acetate Binding Modes: Experimental and Theoretical Studies

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.

Ru-Controlled Thymine Tautomerization Frozen by a k1(O)-, k2(N,O)-Metallacycle: An Experimental and Theoretical Approach

“…On the other hand, the enhanced hydridic character (δ = −16.5) of the chelate trans P,P , k 2 (O,O)-(RuH(CO) (PPh 3 ) 2 THAc) ( 3 ), due to the influence of the dihapto-acetate ligand, and the minimized inter-ligand encumbrance, in agreement with the previous theoretical calculations for the energy of torsion (10 kJ mol −1 ) [ 1 ], are factors which promote both the extra stabilization of 4 and the competitive formation of 5. The resulting cis P,P rearrangement, which was exhibited by the crowded species of 5, was also observed also in the self-aggregated multihapto complex, 4 .…”

“…The latter revealed uncountable conformations due to the mobility of the k 2 (O,O)-side arm, with low energy rotation (10 kJ mol −1 ) around the C-C bond between the methylene spacer and the carboxy unit ( Figure 4 ). Both experimental and theoretical studies of the rearrangement have been detailed in our recent publication [ 1 ].…”

“…The coordination of Ru enables the stabilization of the unstable tautomer through the intramolecular interaction o fH (O-H–––(O)C-ORu) between the tethered carboxy unit and the C2(OH) iminol moiety of C ( Figure 10 ), as suggested by the observed high-shifted signal at δ = 11.2. The intermolecularly bound keto forms of B , which appeared at δ = 8.2, is the typical NH—(O)C Watson–Crick type bond [ 1 ].…”

“…The spectroscopic characterization, including the mass spectra of 5 , has already been reported in previous studies [ 1 ].…”

“…Moreover, in the last 10 years, they have demonstrated remarkable bioactivity as anticancer agents [ 9 , 11 ], ascribable to the exhibited versatility and flexibility (mainly due to the facile cleavage of phosphine ligands and their relocation), but also to their thermodynamic robustness as carriers, due to the function of chelated carboxyl. Recently, we also described the pivotal role of Ru’s coordination in the derivatives of thymine acetate (THAc), even in the absence of electron conjugation, due to the N-methylene spacer between thymine ring and the tethered acetate [ 1 ]. The role of metal coordination and the H-binding interactions network both result in affecting the transfer of H by triggering the transformation from the prevalent (C(O)NH) keto-amino to the rare tautomeric (N=C(OH)) iminol fragment.…”