Chemoenzymatic synthesis of organoselenium(IV) compounds and their evaluation as cysteine protease inhibitors

Abstract

Uma série de organosselenanas foi sintetizada utilizando-se uma metodologia quimioenzimática. Estas organosselenanas apresentam variações na estereoquímica e no halogênio ligado ao átomo de selênio. Devido à reação característica envolvendo compostos de selênio e tióis, estas organosselenanas foram avaliadas como inibidores de cisteíno proteases (catepsinas V e S). As constantes de inibição de segunda-ordem mostraram que a catepsina S é inibida mais rapidamente do que a catepsina V. Pode-se observar que as organosselenanas dibromadas são inibidores mais potentes do que as dicloradas. Desta forma, os resultados obtidos mostram que compostos hipervalentes de selênio podem ser aplicados como inibidores de cisteíno proteases.A series of organoselenium dihalides (organoselenanes) was synthesized from organoselenides using a chemoenzymatic approach. The organoselenanes have variations in their stereochemistry and in the halogen atom bonded to the selenium atom. Because of the unique selenium-thiol chemistry displayed by several organoselenium compounds, the organoselenanes were evaluated as new potential inhibitors of cysteine proteases (cathepsins S and V). By the analysis of the second-order rate constants of the inhibition of cathepsin S and V, it was possible to conclude that organoselenanes inhibited the cathepsin S faster than cathepsin V. It was observed higher inhibitory potencies for the dibromo organoselenanes derivatives than the dichloro analogues. In addition, the present data suggest the use of hypervalent selenium compounds as novel motifs for cysteine proteases inhibitors.

A small-molecule antivirulence agent for treating Clostridium difficile infection

“…It has been proposed, both in cellular systems and in vivo, that ebselen acts as an electrophilic modifier of plasma and intracellular proteins through selenosulfide conjugation with cysteine residues (45). Although the potential of ebselen to act as an enzyme inhibitor is somewhat unclear, selenium-containing compounds have been shown to act as inhibitors of cysteine proteases (46). We chose ebselen as our lead compound because it has a clean safety profile in humans, and human pharmacokinetic data are available, thus giving it high potential for clinical translation.…”

Structure–activity relationships of hypervalent organochalcogenanes as inhibitors of cysteine cathepsins V and S

“…4). 29 The first observation, by this comparison, is the opposite selectivity. While organotelluranes 1-6 inhibited cathepsin V faster than cathepsin S, in the case of organoselenanes cathepsins S was preferentially inhibited than cathepsin V. By consider the k 2 of organotelluranes 1-6 and organoselenane 7-12, it is possible to distribute the compounds 1-12 in three groups according to the combinations of the chalcogen (Y = Se and Te) and halogens (X = Cl and Br) and correlate them with the inhibition constants.…”

“…These assays were useful to identify the relevance of the chalcogen atom for the profile of the compounds 1-6 as inhibitor of cathepsins V and S. When these results are compared with that obtained to organoselenanes cogeners it is evident that the chalcogen atom is fundamental for the performance of the inhibitors since it was observed that the percentage of inhibition of cathepsins V and S by organotelluranes (1-6) are around 90 % while for organoselenanes the inhibitory activities were about 70-80 % at the same conditions. 29 Conclusions regarding the contributions of halogen and details involving the stereochemistry of these compounds could not be made by these tests. Thus, the second-order inactivation rate constants (k 2 ) of cathepsins V and S for compounds 1-6 were determined, then all structural factors that influence each compound activities against these enzymes were identified.…”

Hypervalent organochalcogenanes as inhibitors of protein tyrosine phosphatases

“…Recent investigations have shown that organoselenanes and organotelluranes are very potent inhibitors of cysteine cathepsins, a thiol-dependent enzyme. 12 The affinity between the sulfur-moiety from the catalytic site of these enzymes and chalcogen atom (especially tellurium) makes favorable the formation of a σ Y-S-Enz (Y = Se and Te, S-Enz = thiol-dependent enzyme) bound in the inhibitory process. Due to their distinct molecular arrangement and charge distribution, the chalcogen, present in these hypervalent compounds, accommodates a positive charge and consequently, become more electrophilic than their chalcogenides congeners.…”