Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

We investigated the reactions between substituted α,β‐unsaturated carbonyl compounds (Michael systems) and thiols by computations as well as chemoassays. The results give insight into variations in the underlying mechanisms as a function of the substitution pattern. This is of interest for the mechanisms of inhibition of the SARS coronavirus main protease (SARS‐CoV M^pro) by etacrynic acid derivatives as well as for the excess toxicity of substituted α,β‐unsaturated carbonyl compounds. This study compares possible reaction courses including 1,4‐addition followed by a ketonization step, and underscores the importance of a base‐catalyzed step for the reactivity of thiol groups in enzymes. Phenyl and methyl substituents at the Michael system decrease the reactivity of the electrophilic compound, but chlorophenyl substituents partly recover the reactivity. Computations also indicate that electron‐pushing substituents lead to a change in the reaction mechanism. The conformation of the Michael system is also found to significantly influence reactivity: the s‐cis conformation leads to higher reactivity than the s‐trans conformation. The computed data explain the trends in measured inhibition potencies of substituted α,β‐unsaturated carbonyl compounds and of reaction rates in chemical assays. They also indicate that the reversibility of inhibition does not stand in contrast to the formation of a new covalent bond between inhibitor and protease.     

Rheology and colloidal structure of silver nanoparticles dispersed in diethylene glycol

Rheological behavior of agglomerated silver nanoparticles (~ 40 nm) suspended in diethylene glycol over a wide range of volumetric solids concentrations (? = 0.11–4.38%) was studied. The nanoparticle suspensions generally exhibited a yield pseudoplastic behavior. Bingham plastic, Herschel–Bulkley and Casson models were used to evaluate the shear stress-shear rate dependency. Analyzing the effect of silver concentrations on the yield stress and viscosity of the suspensions followed an exponential form, revealing an increase in the degree of interparticle interactions with increasing solid concentrations. Fractal dimension (D_f) was estimated from the suspension yield stress and ? dependence, and was determined as D_f = 1.51–1.62 for the flocculated nanoparticle suspensions. This suggested that the suspension structure was probably dominated by the diffusion-limited cluster–cluster aggregation (DLCA) due mostly to the strong attractions involved in the interparticle potentials. Maximum solids concentration of the suspensions was determined to be ?_m = 11%.     

Bioorganic and bioinorganic chemistry

The interdisciplinary projects in bioinorganic and bioorganic chemistry of the Department of Chemistry, University of Basel led to the preparation of new systems that mimic biologically important processes and to the discovery of compounds from natural sources which are very promising with respect to medical applications. The advances in these areas are reported here.     

Selective oxidation of alcohols by combinatorial catalysis

High-throughput synthesis and screening of polyoxometalate (POM) and supported-metal libraries have been developed for the selective aerobic oxidation of alcohols to the corresponding aldehydes/ketones in the liquid phase. Libraries consisting of 96 catalysts were prepared in multi-well reactors and screened for catalytic activity using TLC, GC and NMR detection methods. Promising hits identified in the high-throughput primary screens were successfully scaled up and optimized in conventional laboratory test units. Isolated yields confirm high selectivities of more than 90% with quantitative conversions. Substrates tested include primary and secondary alcohols. Specific results will be presented for hydroxymethyl-substituted heterocycles and bicyclo-octanols.