Research interests


Drug Design, Drug Analysis, and Drug Characterisation

Drug research is presently undertaken by two different approaches. On one hand, automated synthesis, high-throughput screening and robotization are employed to find and optimize lead structures. On the other hand, progress is sought through a detailed understanding of the molecular mechanisms of drug action. The modern organic-synthetic and bioanalytical methodology permits to define, observe and engineer more and more precisely the requirements for a drug molecule and the path it takes in the body. For reasons of cost and ease of production and application, 'small' drug molecules are still the molecular entities of choice.

Physiological processes are being elucidated on a molecular level. This helps to define targets for possible therapeutic interventions. The search for new active entities will increasingly start from this knowledge base. This approach can be summarized by the term biomimesis. We look for biomimetics, viz. both of the biopolymers (carbohydrates, nucleic acids, proteins) and of the low-molecular transmitter substances and key metabolites.

The analysis of the chemistry of physiological and pathological processes has to be complemented by an analytical characterization of the drug candidates, including scalar (solubility, lipophilicity etc) and vectorial (reactivity, 3D structure) attributes.

In our group, we analyse the concept of biomimesis from the medicinal-chemical standpoint of view. We look for molecules with special functionalities or constitutional or configurational peculiarities with the aim of exploiting their chemical distinctiveness for pharmaceutical purposes. Commencing with new chemical entities that are 'special' in some respect, or from a hitherto overlooked chemical 'speciality' of a drug candidate, we hope to arrive at new drug lead structures or an improved understanding of a mechanism of action.

The following are research topics we have focussed on:


1. Mimics of arachidonic acid

1.1Nonsteroidal antiinflammatory drugs (NSAID) inhibit the oxidation of arachidonic acid by COX, and this is supposed to at least partly cause their analgetic and antiphlogistic action. The COX inhibitory potency of arylpropionic and arylacetic acid derivatives is caused by the fact that they mimic arachidonic acid. Since arachidonic acid derivatives were found to be endogenous cannabinoid ligands, to us it seemed likely that COX inhibitors or metabolites of them may interact with the cannabinoid receptors and cannabinoid system. We have prepared a number of ethanolamides and glycerolesters of profens in order to test their possible binding affinity at cannabinoid receptors.

1.2 Extracts of chamomile (Matricaria recutita L.) and yarrow (Achillea millefolium s.l.) possess anti-inflammatory properties. Chamazulene carboxylic acid (CCA) is a degradation product of sesquiterpene lactones from Asteraceae. We showed CCA to be a naturally occuring profen and thus to be an arachidonic acid mimic. We elucidated its configuration, stability, anti-inflammatory effectiveness in animal models, and mechanism of action. We found that it is a selective cyclocoxygenase-2 inhibitor. After oral application of matricin, the precursor of CCA, to human volunteers, we showed that considerable plasma levels of CCA resulted. We now focus on establishing an animal model of inflammation so as to compare chamomile constituents, mixtures of them, chamomile extracts and extracts of related Asteraceae, with the ultimate goal of defining an anti-inflammatory chamomile preparation.


2. Anti-inflammatory glycosides

The modern use of willow bark focuses on salicin, the precursor of salicylic acid and its analgesic, anti-inflammatory and antipyretic activity. To date, the effect of salicin has not been understood fully. Salicylic acid is known to be the active metabolite of salicin, but the enzymatic and oxidative conversions in humans are only based on assumptions. It is assumed that beta-glucosidases are essential for the enzymatic conversion of salicin. In humans, there are much fewer beta- than alpha-glucosidases. We investigate the possibility that alpha-glucosides lead to a faster increase of aglyca in blood than the naturally occuring beta-glucosides. For this reason we synthesise different alpha-glucosides of salicin and salicylic acid. Another important glucoside of willow bark is salicortin, one of the main precursors of salicin in the plant. Salicortin contains a cyclohexenecarboxylic acid moiety. We report conditions that convert this moiety into a salicylic acid residue instead of discarding it during usual extract preparation procedures via hydrolysis and decarboxylation.


3. Protopine alkaloids

This group of alkaloids, mainly found in certain tribes of the Papaveraceae, features a fascinating ten-membered ring system with a ketone and amine moiety opposite to each other. Medium-sized rings are semi-flexible, rendering them interesting scaffolds for agonists rather than antagonists. The protopines have not been profiled pharmaceutically in spite of the fact that several of them have a range of activities. We explore synthetic gateways to them, especially to obtain rare or semi-synthetic, new derivatives.


4. In vivo and ex vivoanalysis and reactions of drug substances

We Much has been published concerning the fate and reactions (mechanism of action) of drug substancesin vitro.Much is still to be done as to the actual reactions in living organisms, esp. in man. We are establishing methodology, mainly microbore HPLC and GC-MS, to analyse the latter processes and have begun with a superficially simple yet interesting model substance: caffeine and its oxidation and demethylation metabolites. What is the role of hydroxymethylparaxanthine? What are the plasma level curves after application of caffeine from different sources?


5. Classification of drug substances according to their mechanism of action

This is a theoretical medicinal chemical approach we have taken in our seminars. We have compiled and published a list of one or more drugs of almost every approved drug type ordered by target: "Drugs, their targets, and the nature and number of drug targets" (Nature Rev. Drug Discov. 2006, 18, 5, 821-834). This comprehensive review discusses the question on the definition of a target in times of system-biological considerations and concludes as follows: "In situations in which the dynamic actions of the drug substance stimulate, or inhibit, a biological process, it is necessary to move away from the descriptions of single proteins, receptors and so on and to view the entire signal chain as the target. […] An effective drug target comprises a biochemical system rather than a single molecule."


6. Planar chiral molecules as drug candidates

We have found the first example of different activity for planar chiral enantiomers, and have prepared and tested beta-lactam antiinfectives with a planar chiral side chain.


7. Peptidomimetics

We found that in unsubstituted lactams, the 6-membered ring (delta-valerolactam) is hydrolyzed equally fast as beta-propiolactam. Penicillins are hydrolyzed 10³ times faster than beta-propiolactam. With these analytical results, we further analysed the correlation of hydrolytic lability and structure in beta-lactams and have started the synthesis of penicillin analogues with a valerolactam system.

Cooperations

  • Dr. Gerhard Fürstenberger, Research group Eicosanoids und tumor progression, Deutsches Krebsforschungszentrum, Heidelberg
  • Dr. Yves-Yannick Ford, Horticultural Research International, Kent, UK
  • Dr. Aron Lichtman, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
  • Prof. Dr. Vincenzo Di Marzo, Endocannabinoid Research Group, Consiglio Nazionale Delle Ricerche, Pozzuoli, Italy
  • Prof. Dr. Rolf Nüsing, Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Frankfurt/M.
  • Dr. Stefan Zimmermann, Institut für Medizinische Mikrobiologie und Krankenhaushygiene der Philipps-Universität, Marburg
  • Prof. Bernhard Watzer, Mutter-Kind-Zentrum, Zentrum für Kinder- und Jugendmedizin, Pädiatrische Forschung, Labor für Instrumentelle Analytik, Marburg
  • Prof. Dr. Hannu Raunio, Institute for Pharmakology and Toxikology, University of Kuopio, Finland
  • Merckle GmbH, Blaubeuren
  • Robugen GmbH Pharmazeutische Fabrik, Esslingen