The Interaction of Molybdenum Complexes and Polyoxometalates with DNA Models

Sánchez-González, A.; Bandeira, N.; Gil, A.*; Calhorda, M. J. Advances in Health and Disease, Amies, W., Ed. Nova Science Publishers, Inc.: New York, 2022; volume 53.

Molybdenum, known since 1778, is a 4d transition element relatively abundant, and plays an important biological role, being found in several enzymes. It can gain or lose electrons, forming stable compounds for a wide range of oxidation states. This chapter on our work in molybdenum is divided into two parts. The first addresses Mo(II) complexes of the family [Mo(C3H5)Br(CO)2(LL)], where LL represents a 1,10-phenanthroline (phen) ligand or related ligands. They are cytotoxic towards several human tumor cell lines. A computational approach allowed to study their interaction with duplex DNA (dDNA) and G-quadruplexes (GQ), in order to unravel the nature of the biological activity. The two isomers, Eq and Ax, of [Mo(C3H5)Br(CO)2(phen)] intercalate between base pairs of dDNA through phen as found experimentally. Computational studies highlighted not only the importance of the pi-pi stacking through phen, but also the important role of the ancillary ligands. The complex prefers the intercalation via the minor groove because the ancillary ligands are involved in stabilizing weak interactions not only with base pairs, like in the case of the intercalation through the major groove, but also with the sugar and phosphate backbone. On the other hand, in the interaction of the [Mo(C3H5)Br(CO)2(phen)] complex with GQ, the Eq and Ax isomers behave differently. More negative (attractive) interaction energies were calculated for the Eq isomer than for the Ax isomer. In the most stable structures with the Eq isomer, the metal complex interacts from outside the GQ either intercalating through the phen ligand between base pairs of the GQ or by means of the allyl group and the Br halogen atom. Nevertheless, when the solvent effects are taken into account, the GQ systems containing the Ax isomer become the most stable. Surprisingly, it was found that the Ax isomer interacts by means of end-stacking totally inside the non-canonical DNA secondary structure in which both the G-tetrads of the GQ and the subsequent adenine tetrads interact with the Ax isomer of the [Mo(C3H5)Br(CO)2(phen)] complex. In addition, the interaction energies between [Mo(C3H5)Br(CO)2(phen)] and GQ are more negative with or without considering solvent effects, than when interacting with dDNA, which suggests that this complex might be more selective for the interaction with GQ. In the second part, Mo(VI) species will be addressed, either polyoxometalates (POMs) derived from [Mo7O24]6- in solution or [MoO2Cl2(LL)] complexes (L = monodentate ligand). Both are involved in the catalytic cleavage of the phosphoester bond. The computational study dealt with para-nitrophenylphosphate (pNPP), a simpler model of the phosphoester bond in DNA. The most remarkable results obtained from these studies were that, in the rich chemistry of Mo-oxo species in solution, a binuclear Mo-oxo species is formed in situ in the reaction media and it is responsible for the catalytic hydrolysis of the phosphoester bond in pNPP. It was also found that starting from a simpler Mo oxide containing one metal center of Mo or starting from the [Mo7O24]6- polyoxomolybdate with seven Mo centers, it is possible to evolve to such binuclear active species [Mo2O8H4]0 participating in the important reduction of the high barrier for the phosphoester hydrolysis. This barrier is mainly attributed to the repulsion of the negative phosphate environment with the negative charge of the nucleophile. The formation of the proposed null-charged binuclear [Mo2O8H4]0 species would explain the easy approach to the negatively charged environment of the phosphate.