Research Interests of
Prof. Dr. P. Rüedi
General
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.
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
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.
Selected
Posters
Last update: 07-July-2009 PR