Optimierung und Anwendung des Ligandenfischens an antiplasmoidalen Targets (DXR und GDH) und Thrombin

Auf der Suche nach Leitstrukturen liegt nach Versagen der kombinatorischen Chemie der Fokus heute wieder vermehrt auf Naturstoffen, aus denen schon in der Vergangenheit viele Leitstrukturen hervorgebracht werden konnten. Dabei folgt die Indikation von 74% der aus Pflanzeninhaltsstoffen entwickelten...

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Bibliographic Details
Main Author: An, Pia Konstanze
Contributors: Matusch, Rudolf (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2006
Pharmazeutische Chemie
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Table of Contents: After the failure of combinatorial chemistry the search for new leads is focused on natural products again as they yielded a lot of leads in the past already. The indication of 74% of the drugs developed from plants follows the ethnopharmacological usage of those. Therefore plants are a promising starting point for the determination of new drugs. Within the scope of this thesis miscellaneous plant extracts were examined by both the method of fishing of ligands for possibly new antiplasmoidal compounds and an amidolytic assay for thrombin inhibiting compounds. After AIDS malaria is the next most deadly disease in developing countries. The number of malaria cases in industrialised nations is rising though. Reasons are found in insufficient prophylaxis and the so-called airport malaria. Because of the high resistance against available drugs in the meantime, there is a permanent need of new antimalarials. Current research concerns mainly with the locating and investigation of new targets. For the present work two targets named DXR and GDH were available. These targets should yield potential selective drugs as they do not occur in human beings or are only slightly similar to those found in human beings. Deoxy-xylulosephosphate reductoisomerase (DXR) is an enzyme of the alternative isoprenoid-biosynthesis pathway. It was shown that metabolites of clomazone are generated in garden cress after treatment with this herbicide. These metabolites showed both interactions with DXR by fishing of ligands and inhibition of an activity assay. After structure determination they could be promising compounds against plasmodia. Glutamate dehydrogenase (GDH) plays a major role in the redox-homeostasis of plasmodia. The homology of parasitic and human sequence is minor and besides erythrocytes do not contain an own GDH but the parasitic. The present thesis supports the assumption of the impairment of parasitic redox-homeostasis by garlic disulfides. Furthermore an interaction of GDH with probably a vinyldithiin could be shown whereas no antiplasmoidal activity is known for vinyldithiins so far. While the population in developing countries is suffering mainly from infectious diseases the population of countries with a certain standard of living caused by improved nutrition and hygiene is struck particularly by cardiovascular diseases. Main reasons are a wrong nourishment, insufficient work out and smoking. In industrialised countries the main cause of death is thrombosis as complication of atherosclerosis. In 2020 the major global causes of deaths apart from Black Africa will be ischemic heart conditions and cerebrovascular diseases. Today available anticoagulants are inapplicable in populace uncritically. They are either difficult to handle or need an unfavourable method of application. In February 2006 the drug ximelagatran, the first orally available thrombin inhibitor for the German market, was recalled again. Hence there is a constant vast demand for new anticoagulants, especially with an oral availability. Therefore officinal plants were used for the search of new thrombininhibitors. Within this thesis an inhibition of human thrombin by extracts of apiaceae could be shown. The active principle was determined as free fatty acids, in particular linolenic acid and petroselinic acid. In this context the carboxylic function was discovered to be essential for the inhibiting effect of fatty acids on human thrombin. Further on cyclooxygenase inhibitors were testet and indometacine was found to inhibit human thrombin as well. Finally during this work the method of fishing of ligands was optimised with human thrombin as target.