Strukturbasierte Entwicklung von Inhibitoren der humanen Tyrosinase und der Farnesyltransferase

Synthesis of novel inhibitors of human tyrosinase was carried out in close collaboration with the groups of Prof. Klebe and Prof. Röhm. The work was part of an industrial project funded by Beiersdorf. The crystal structure of the human enzyme has not been solved up to now. Therefore a homology model of the substrate binding site was generated for the purpose of rational drug design. The binding site model was on crystallographic data of the tyrosinase of Streptomyces castaneoglobisporus and the catechol oxidase of Ipomea batatas. Screening of CSD-data-base for di-copper-binding-motifs revealed several potential enzyme inhibitors, whose development and optimization should result in potential compounds in near future. The goal of the search was for structures, whose inhibitory principle should not exclusively on the copper-chelating group. Directed interactions with the side chains of certain amino acids in the substrate binding site should additionally enhance the inhibitory strength. Subsequent optimization of several postulated compounds was not successful, due to overall low inhibitory potential. Due to these results expectations were low to find the desired inhibitors. Therefore the synthesis of three of the four proposed compound classes was discontinued. Further lead structures were derived from the structure of the well-known tyrosinase inhibitors kojic acid (12) and (L)-Mimosine (15). Starting from these compounds their molecular scaffold was successively varied and enhanced. On the basis of results important structure-activity-relationships were discovered and subsequently verified by docking studies. It was shown that the hydroxymethylene structure of kojic acid (12) extents into a lipophilic area of the substrate binding site of the enzyme. Therefore this structural element was replaced by a thioether. The sulphur-containing derivative 229 was obtained, with has a Ki-value of 18.6 µM. This renders it a more potent inhibitor human tyrosinase than standard hexylresorcinol (19)(Ki = 26.1 µM). The second part of the thesis dealt with the synthesis of farnesyltransferase inhibitors (FTI´s) of Plasmodium falciparum. In contrast to FTI´s, which were developed earlier in the group of Prof. Schlitzer, inhibitors were based on a sulphonamide partial-structure and should be more drug-like. Previous docking-studies proposed starting compound 335, whose molecular scaffold should be successively varied and optimized. In this process sulphonamide-derivate 389 was obtained, whose inhibitory activity in-vitro testing was more potent by a factor of 20 than the lead compound 335. In the course of the improvement of 335 the benzyl substituent was exchanged for aromatic or a diversity of other side chains. These substituents contained terminal groups with polar and/or basic character. Moreover the metal tie, the imidazole containing part of the molecule, was modified. Both variations led to substances, which were more potent by a factor of 5 respectively 10 than lead compound 335 (IC50 = 1200 nM). Considering the preliminary results it can be said, that inhibition of the farnesyl-transferase is a promising concept for the optimization of new drugs to treat Malaria infections. The long-term objective is the development of inhibitors with improved inhibitory activity.