Group Leader:

Prof. P. Rüedi

Group Members:

OCI-Phonebook#Rüedi

Research Topics Acetylcholine Mimetics Enzymatic Reactions Natural Products Organophosphorus Compounds Phytochemistry Spectroscopic Methods, 31P-NMR Stereochemistry

Research Interests of Prof. P. Rüedi

The research activities of P. Rüedi's group focus on the two main subjects phytochemistry and organophosphorous chemistry, both with a direct link to life sciences' problems. The general goal is to contribute to the understanding of chemical reaction mechanisms, in particular molecular interactions, which are the basis of essential physiological processes. Main emphasis is placed on stereochemical implications of enzymatic reaction pathways.

Organophosphorous Chemistry; Serine Hydrolases

In that area the group is engaged with the spectroscopic investigation of the catalytically active site of acetylcholinesterase and of related serine hydrolases (e.g. Chymotrypsin). Although fundamental structural parameters of these essential enzymes have been disclosed recently by X-ray analyses, no consistent understanding of the (stereo)chemical reaction mechanisms and the dynamics of the catalysis exists. In the current project the regio- and stereochemical course of the inhibition with organophosphorous compounds is investigated, with special emphasis being placed on the covalent binding interactions between inhibitors and the enzymes. For this purpose, novel diastereo- and enantiomerically pure N-heterocyclic organophosphates of the cis- and trans-decalin type with fixed configurations and conformations (rigid acetylcholine mimics) are prepared by enantioselective synthesis and fully characterized. Their inhibitory action towards acetylcholinesterase and related hydrolases as well as postinhibitory phenomena are being studied by kinetic and NMR-spectroscopic methods. Besides novel analytical knowledge, the synthesis of such compounds also affords insight into open questions of general organic chemistry concerning nucleophilic displacement reactions at phosphorus and of absolute configuration. It is a further aim to design new compounds as 'slow', reversible inhibitors of the enzyme which might be used in the therapy of several diseases such as glaucoma, Alzheimer's dementia and other cholinergic-related impairments.

 

Phytochemistry

The phytochemical topic is mainly concerned with antioxidant activity-guided isolation, structure elucidation and synthesis of genuine constituents of African and Asian medicinal plants. Due to the evidence of free radical-mediated pathological processes, natural products which inhibit the peroxidation of lipid membranes are currently of interest. The structurally various compounds that have been isolated are being tested as potential radical scavengers (antioxidants), inhibitors of enzymes of the arachidonic acid metabolism (cyclooxygenase and lipoxygenase), allergens and DNA-cleavage reagents with the aim of establishing structure-activity relations. Recently, a series of novel long-chain alkyloxy(o) catechols of the [n]-gingerol type has been isolated. Enantioselective syntheses of optically active compounds are performed in order to investigate the influence of the chirality in the alkyloxy side-chain with respect of the enzyme inhibition. Other Keywords are: antioxidants, antimicrobials, inhibitors of lipoxygenase and acetylcholinesterase, as well as anti-malaria, anti-tumor, and anti-inflammatory activities.
Another phytochemical project deals with mechanistic investigations of tri- and tetracyclic diterpenoids where biomimetical transformations, rearrangements and the elucidation of stereochemical pathways are being studied. In this connection, the stereochemistry of the nucleophilic ring-opening in spiro-cyclopropanes has been cleared. Work on the characteristic reactions of quinone methides and their biological significance has lead to the chemistry of anthocyanins, where in the complex equilibrium mixture of the compounds the quinone methide forms are colour-determining. In the course of recent investigations on the stabilization of such chromophores in Nature (co-pigmentaion, which is a fundamental natural principle), genuine pigment/co-pigment complexes have been isolated and characterized. The synthesis and spectroscopic analysis of model systems enable the investigation of novel aspects of such intermolecular associations.

 

Recent Results

The stereochemistry of the irreversible inhibition of [delta]-chymotrypsin by racemic and optically active, axially and equatorially P-substituted cis- and trans-decalin type organophosphates has been investigated.
Synthesis and Kinetic Characterization of Rigid Acetylcholine Mimetics; X-Ray Evidence of the Anomeric Effect.
Evidence of a Stereospecific 3-2 Hydride Shift in an Unexpected Transformation of a Tetracyclic Diterpenoid.

The Research Goals of Prof. P. Rüedi as PDF-document (530 kB)

Selected Publications

Research Interests

Current Projects

Positions Available

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