Cyclopropenone-containing cysteine proteinase inhibitors. Synthesis and enzyme inhibitory activities

By focusing on the amphiphilic properties of cyclopropenone (e.g. a good el ectrophile and a precursor for a stable 2 pi-aromatic hydroxycyclopropenium cation), a new class of cysteine proteinase inhibitors containing a cyclop ropenone moiety was designed. For the purpose of the present research, we n eeded to devise a new method to introduce a peptide-related moiety as a sub stituent on the cyclopropenone residue. We investigated the reaction of met alated cyclopropenone acetal derivatives (2, R-2 = metal) with N-protected alpha-aminoaldehydes 4 to obtain the adduct 5, and succeeded in the prepara tion of highly potentiated cysteine proteinase inhibitors 8 after several s teps transformations. They showed strong inhibitory activities only to cyst eine proteinases such as calpain, papain, cathepsin B, and cathepsin L and not to serine (e.g. thrombin and cathepsin G) and asparatic protainases (e. g. cathepsin D). Kinetic studies indicated that they are competitive inhibi tors, and by the examinations of their inhibitory mechanism it became clear that they are reversible inhibitors. (C) 1999 Elsevier Science Ltd. All ri ghts reserved.