Verwendung metallorganischer Verbindungen als Inhibitoren für Serinproteasen

Organometallic compounds are capable of shaping spatial globular structures by extension of the coordination number compared to organic substances. MEGGERS et al. used this capability to successfully fill in the chemical space in active sites of protein kinases. In this dissertation organometallic serine protease inhibitors were designed and examined. The metal center on one hand had structural properties to adjust the ligand sphere, but on the other hand photochemical features were used to develop CALI inhibitors (chromophore assisted light inactivation). Several basic and non-basic ligands were synthesized and transferred into metal complexes of octahedral and pseudo octahedral geometry. Out of a series of different designs of basic inhibitors an enantiomerically pure octahedral coordinated iridium phenylpyridine complex was found with an IC50 of 1.01 μmol/L for Trypsin. However, by using non-basic and less affine ligands out of a library a pseudo octahedral coordinated ruthenium cyclopentadienyl complex was identified as a Thrombin inhibitor with an IC50 of 40 μmol/L, showing no affinity for Trypsin in the studied concentration range. By using the CALI-technique where a chromophore attached to the inhibitor produces singlet oxygen the most potent inhibitors for trypsin were obtained. Several irradiation times were examined and after irradiaton for 120 min an IC50 of 101 nmol/L was determined for a bipyridine complex.