Research Interests
and Publications 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.
2010 – actual
Selected Posters (pdf-files)
Last update: 22-April-2013 PR