Entwicklung von anti-parasitär wirksamen Farnesyltransferaseinhibitoren mit Benzophenon-Grundstruktur

Das Enzym Farnesyltransferase katalysiert mit der Übertragung eines Farnesylrestes auf eine spezifische C-terminale Aminosäuresequenz den ersten und entscheidenden Schritt in der posttranslationalen Modifikation vieler Proteine. Farnesylierte Proteine spielen eine entscheidende Rolle bei der Zellpro...

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Bibliographic Details
Main Author: Kettler, Katja
Contributors: Hanefeld, Wolfgang (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
Online Access:PDF Full Text
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Table of Contents: Farnesyltransferase catalyzes the transfer of a farnesyl residue to a specific C-terminal amino acid sequence. This transfer is the first and most important step in the posttranslational modification of proteins. Farnesylated proteins are important in cell proliferation, gene expression, changes of the cyto skeleton and production of second messengers. Therefore, inhibition of protein farnesylation has received major attention in the development of anti-cancer drugs. But the main focus does not only concentrate on the design of anti-tumor-therapeutics alone but also on the development of new anti-infective drugs. Protein prenylation occurs in Plasmodium falciparum (causative agent of Malaria tropica), Trypanosoma brucei (sleeping sickness), Trypanosoma cruzi (Chagas disease) and Leishmania major (Leishmaniasis). Thus, the main focus of this dissertation is the development of anti-parasitic farnesyltransferase inhibitors with a benzophenone-based core structure in a structure-based approach. These inhibitors exhibit high in vitro-activity against Plasmodium falciparum and Trypanosoma cruzi with IC50-values in the low nanomolar range. Further optimisation resulted in the first farnesyltransferase inhibitors with in vivo-activity against Plasmodium falciparum described in literature. Likewise farnesyltransferase inhibitors with oral in vivo-activity against Trypanosoma cruzi have been synthesized. First evaluation of these compounds against Leishmania-species show promising results.