Synthese S/N-funktionalisierter Dipeptide als Hemmstoffe von Zinkendoproteasen

A series of new potential inhibitors of the zinc endopeptidases thermolysin (TLN) and the matrix metalloproteinases (MMPs) was developed. Following a substrate-based approach a dipeptide was used as a scaffold, which was linked with functional groups with potential zinc-binding properties. The groups were preferably based on S-/N-functional structures. Preferably Leu-Phe and Leu-Trp served as a dipeptide-scaffold. Beside hydroxamic acid, carboxylic acid and thiol a number of sulfonamides, sulfinamides, sufinylureas, sulfonylureas, sulfonimidoylureas, sulfodiimines, as well as the sulfoximidocarbonyl group, the sulfodiimidocarbonyl group and the N-sulfamoyl group were used as potential zinc-binding groups. The reaction of different amino acid esters and dipeptides with diphenyl-N-sulfamoyl-iminocarbonate led to the introduction of the N-sulfamoyliminophenoxymethyl group which was further converted to the N-sulfamoylcarbamimidoyl group. The reaction of the dipeptides with diphenyl-N-cyaniminocarbonate led to N-substituted cyaniminophenoxymethyl dipeptides, which could be cyclized to 3-amino-1,2,4-triazoles, 3-amino-1-methyl-1,2,4-triazoles and 5-amino-1-oxa-2,4-diazoles. The hydroxamic acid, carboxylic acid, thiol and sulfonamides, sulfinyl ureas and the 3-amino-1,2,4-triazole inhibited the matrix metalloproteinases in a micromolar range. A sulfonimidoylurea showed a weak inhibition of thermolysin in a micromolar range. The N-sulfamoyl dipeptides were tested against the human carbonic anhydrases I and II and showed inhibitory properties in a micromolar range.