Synthesis, biological evaluation and metadynamics simulations of novel N-methyl ß-sheet breaker peptides as inhibitors of Alzheimer's ß-amyloid fibrillogenesis.

Several scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of ß-amyloid proteins in the brain. Because Aß is self-assembling, one possible design strategy is to inhibit the aggregation of Aß peptides using short peptide fragments homologous to the full-length wild-type Aß protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called ß-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.

Photochemical C-H Amination of Ethers and Geminal Difunctionalization Reactions in One Pot.

A mild, atom-economic, and metal-free α-C-H amination of ethers using relatively stable nonafluorobutanesulfonyl (nonaflyl, Nf) azide as the aminating reagent to give N-sulfonyl hemiaminals is reported. This enables unprecedented C(sp3 ) difunctionalization reactions, leading to diverse functionalized amino group containing compounds starting from simple ethers in one pot.