Palladium‐Catalyzed Fluorosulfonylvinylation of Organic Iodides

A palladium‐catalyzed fluorosulfonylvinylation reaction of organic iodides is described. Catalytic Pd(OAc)₂ with a stoichiometric amount of silver(I) trifluoroacetate enables the coupling process between either an (hetero)aryl or alkenyl iodide with ethenesulfonyl fluoride (ESF). The method is demonstrated in the successful syntheses of eighty‐eight otherwise difficult to access compounds, in up to 99 % yields, including the unprecedented 2‐heteroarylethenesulfonyl fluorides and 1,3‐dienylsulfonyl fluorides.     

A Computational Method for Unveiling the Target Promiscuity of Pharmacologically Active Compounds

Drug discovery is governed by the desire to find ligands with defined modes of action. It has been realized that even designated selective drugs may have more macromolecular targets than is commonly thought. Consequently, it will be mandatory to consider multitarget activity for the design of future medicines. Computational models assist medicinal chemists in this effort by helping to eliminate unsuitable lead structures and spot undesired drug effects early in the discovery process. Here, we present a straightforward computational method to find previously unknown targets of pharmacologically active compounds. Validation experiments revealed hitherto unknown targets of the natural product resveratrol and the nonsteroidal anti‐inflammatory drug celecoxib. The obtained results advocate machine learning for polypharmacology‐based molecular design, drug re‐purposing, and the “de‐orphaning” of phenotypic drug effects.     

Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue

Synthetic insulin analogues with a long lifetime are current drug targets for the therapy of diabetic patients. The replacement of the interchain disulfide with a diselenide bridge, which is more resistant to reduction and internal bond rotation, can enhance the lifetime of insulin in the presence of the insulin-degrading enzyme (IDE) without impairing the hormonal function. The [C7U^A,C7U^B] variant of bovine pancreatic insulin (BPIns) was successfully prepared by using two selenocysteine peptides (i.e., the C7U analogues of A- and B-chains, respectively). In a buffer solution at pH 10 they spontaneously assembled under thermodynamic control to the correct insulin fold. The selenoinsulin (Se-Ins) exhibited a bioactivity comparable to that of BPIns. Interestingly, degradation of Se-Ins with IDE was significantly decelerated (τ_1/2≈8 h vs. ≈1 h for BPIns). The lifetime enhancement could be due to both the intrinsic stability of the diselenide bond and local conformational changes induced by the substitution.