Despite being a very strong oxidizing agent, most organic molecules are not oxidized in the presence of O2 at room temperature because O2 is a diradical whereas most organic molecules are closed‐shell. Oxidation then requires a change in the spin state of the system, which is forbidden according to non‐relativistic quantum theory. To overcome this limitation, oxygenases usually rely on metal or redox cofactors to catalyze the incorporation of, at least, one oxygen atom into an organic substrate. However, some oxygenases do not require any cofactor, and the detailed mechanism followed by these enzymes remains elusive. To fill this gap, here the mechanism for the enzymatic cofactor‐independent oxidation of 3,5‐dihydroxyphenylacetyl‐CoA (DPA‐CoA) is studied by combining multireference calculations on a model system with QM/MM calculations. Our results reveal that intersystem crossing takes place without requiring the previous protonation of molecular oxygen. The characterization of the electronic states reveals that electron transfer is concomitant with the triplet–singlet transition. The enzyme plays a passive role in promoting the intersystem crossing, although spontaneous reorganization of the water wire connecting the active site with the bulk presets the substrate for subsequent chemical transformations. The results show that the stabilization of the singlet radical‐pair between dioxygen and enolate is enough to promote spin‐forbidden reaction without the need for neither metal cofactors nor basic residues in the active site.

Chiral pyrazolones with a spirocyclic centre at the C4-position are widely found in a large family of medically relevant compounds. In recent years, organocatalysis, particularly that performed with quiral N-heterocyclic...

Oxygenases are a family of enzymes that catalyse the breaking of molecular oxygen with incorporation of, at least, one oxygen atom into an organic substrate. Since molecular oxygen is a diradical and most organic molecules have no unpaired-electrons, reactions catalysed by oxygenases involve changes in the spin state of the system that are forbidden in non-relativistic quantum theory. To overcome this limitation, oxygenases usually require metal or redox cofactors for catalysis. Intriguingly, some oxygenases can catalyse oxygen incorporation reactions even in the absence of any cofactor, but the detailed mechanism followed by these enzymes to overcome this limitation is still unknown. In the present work we give insight onto the mechanism for the enzymatic cofactor-independent oxidation of 3,5-dihydroxyphenylacetyl-CoA (DPA-CoA) by the combination of multi-reference calculations on a model system, with QM/MM calculations for the enzymatic reaction. Our results reveal that intersystem crossing takes place without requiring concerted protonation of molecular oxygen. We characterized and identifed the nine concurrent electronic states, showing that a first electron transfer is concomitant with the triplet-singlet transition (intersystem crossing). The enzyme apparently plays a passive role in promoting the intersystem crossing, although spontaneous reorganization of the water-wire connecting the active site with the bulk presets the substrate for subsequent chemical transformations. We believe that our results are fairly general showing that stabilization of the singlet radical-pair state between molecular oxygen and enolates is enough to promote spin-forbidden reaction without the need of neither metal cofactors nor basic residues in the active site.

In spite of being spin-forbidden, some enzymes are capable of catalyzing the incorporation of O 2 ( 3 Σ − g ) to organic substrates without needing any cofactor. It has been established that the process followed by these enzymes starts with the deprotonation of the substrate forming an enolate. In a second stage, the peroxidation of the enolate formation occurs, a process in which the system changes its spin multiplicity from a triplet state to a singlet state. In this article, we study the addition of O 2 to enolates using state-of-the-art multi-reference and single-reference methods. Our results confirm that intersystem crossing is promoted by stabilization of the singlet state along the reaction path. When multireference methods are used, large active spaces are required, and in this situation, semistochastic heat-bath configuration interaction emerges as a powerful method to study these multi-configurational systems and is in good agreement with PNO-LCCSD(T) when the system is well-represented by a single-configuration.

Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.