How molybdenum species cleave the phosphoester bond.

Abstract

Metal species have a great impact on the biochemistry of living systems. It has been reported that polyoxomolybdates exhibit anti-tumor activity similar to that of commercial drugs. However, the mechanism by which these species are effective against cancer has been an elusive topic. It is believed that their activity is related to their interaction with phosphoester' containing biomolecules.Experimental studies have demonstrated that molybdenum species can cause cleavage in different model phosphoester molecules.However, the complex chemistry of molybdates has made these experimental studies difficult to interpret. We used computational methodologies to shed light on the phosphoesterase activity of molybdenum species in different reaction models. The study employed density functional theory to explore the mechanistic details of hydrolysis reactions of phosphate monoesters and diestersin the presence of different molybdenum species.The study results on the speciation of MoO2Cl2(DMF)2 supported the experimental findings that reported DMF release and Mo¿Clbond breakage. Two different NPP hydrolysis pathways were proposed depending on the complex concentration. Lower concentrations disfavoured the formation of polynuclear species, and the hydrolysis proceeded through less favourable mononuclear intermediates. With enough complex concentration, a nucleation process was favoured over the phosphate interaction. After theformation of dinuclear species, the incorporation of NPP and its consequent hydrolysis showed lower energetic barriers than theuncatalysed reaction. We also examined heptamolybdate as it was reported to hydrolyse NPP while its nuclearity decreased.Pentanuclear active species proposed by experimentals showed a higher activation barrier for its hydrolysis and cannot beconsidered as a catalyst. The study proposed a dinuclear compound resulting from heptamolybdate fragmentation as the catalytic species, which decreased the energetic barrier compared to the non¿catalysed reaction. With DNA and RNA models BNPP andHPNP, the calculations supported the experimental findings that heptamolybdate can hydrolyse phosphodiester molecules without fragmentation. With phosphate diesters, the hydrolysis proceeded through more compact mechanisms than with phosphatemonoesters, in which phosphorane structures are formed.The study revealed that the dinuclear species and the heptamolybdate cluster provide a structural motif that catalyses the hydrolysisof these phosphates. The molybdate structure generally augments the electrophilia of the phosphorous atom and can deprotonateand activate the nucleophile, favouring associative mechanisms. This information can aid in designing effective and non¿toxicphosphoesterases.