Silvia Bordoni

Bioactive molecules to Ruthenium coordination

Along the past 10 years, it has been commonly assumed that Ruthenium species have recently shown (A. Castonguay, 2020; R. S. Correa, 2019 and 2020) more effectiveness compared to cis-Platinum compounds in cancer reduction, overcoming the resistance, shown by the common antineoplastic drugs upon longer treatments and by limiting toxic effects towards intact cells. Focusing on the coordinative fashion modes is a primary interest to disclose new relations between Structure – Activity. First of all, it warrants to underline that base-research investigations on the coordination structures exhibited by newly synthesized Ru-complexes are of primary importance to connect structure modulation and the multifaceted anticancer activity. Firstly,  the previous reactions that we studied in the last 8 years by applying the strategy of coordinating nucleobases to the Ru-metal site as effective approach to easily obtain novel bioactive molecules. Metal skeleton rigidity and steric encumbrance both drive the reactions prevalently towards (O,O) coordination, unless the impeded rotation is removed by cleavage of phosphine bond in reciprocal trans-location. By the reduced acidity exhibited by the metal centre, the second ligand addition is consistently more difficult and commonly requires longer times and higher temperature- solicitated reactions. In line with these considerations, monoacetate-coordination and trans-cis isomerization predominate also for steric reasons. Pyrrolil-carboxy acid ligand promotes exclusively (O,O) coordinative fashion mode, in which linearly and parallelly equatorial position prevails. The DFT-calculated planar stereogeometry suggests the occurrence of intramolecular interactions pi-pi stacking between the almost parallel aromatic rings or between the acidic NH-functions and the pi-clouds of the aromatic phenyl phosphine substituents. Other relevant interactions as the CH(sp2) of the phenyl substituents and carbonyl-Ru fragment may be responsible for further stabilizing the diastereoisomers in the kinetic mixtures. The thermodynamic species involves the occurrence of the maximum number of these short-range intramolecular interactions (evaluated as 18 by analyzing the sum of Van der Waals radii versus the measured molecular model interactions It is worth noting that the IR Ru-carbonyl frequency shifts may be considered as probe for the reaction trend, meanwhile hydride NMR signals, designated by very high-shifted signals are evidence of the number of isomeric species obtained. The diasteroisomers are defined by the reciprocal location of the Ru-H and Ru-CO ligands. New perspectives imply the adoption of imuno-modulator ligands as asparagine or the serotonin promoter, namely 5-HTP molecules, to study the benign synergistic effects of natural molecules with the stabilizing action of Ru as carrier metal site and mediator towards living fragments. Many chemical features, as stability and solubility in very polar media, should further be studied to achieve a potential response to anticancer activity. Many biological answers as are claimed by in-vitro and in-vivo tests towards specific tumoral cellular lines. Long way is prospecting to achieve a possible future pharmaceutical drug remedy… but any plausible single path is worthy to be under stepped, to do not leave unattended any new strategies to cope a common enemy of all living beings.