 Hopanes |
| Triterpenoids of the hopane type have been isolated from leaflets of
Cyathea spinulosa ("hego" in Japanese), a tall evergreen tree
fern (more than 4 m high, see picture) with large leaves (2 m long), distributed
in the subtropical and tropical areas of Japan, Taiwan, the Philippines,
China, Burma, India, and Nepal.
As part of an ongoing program dealing with diastereoselective cyclizations using allyl- and propargylsilanes we are interested in developing a new annulation strategy for heterocycles. The required tricyclic furan (DEF subunit) can be synthesized by the use of a novel tandem reaction: Intramolecular [3+2] hetero-annulation of allylsilanes with cyclic 1,3-diketones. Suggested reading: D. Schinzer, G. Panke, J. Org. Chem. 1996, 61, 4496. |
| Epothilones |
| The fascinating biological activities of the epothilones, a new class
of macrolides isolated from the myxobacteria Sorangium cellulosum
by Höfle, Reichenbach and co-workers at the Gesellschaft für
Biotechnologische Forschung (GBF), in Braunschweig, Germany, have created
tremendous excitement in the scientific community. Following a screening
programme aimed at the identification of substances with a taxol®-like
mode of action, in 1995 Daniel M. Bollag and co-workers at the Merck research
laboratories in West Point, PA, found that the epothilones are powerful
cytotoxic agents which function through stabilization of cellular microtubules
in the same mode of action like paclitaxel and its analogues. The
biological activity spectrum of the epothilones is very close to that of
paclitaxel. Both compounds probably compete for the same receptor, paclitaxel
being even displaced from the binding site by the epothilones. They show
similar kinetics in in vitro tests and provide closely similar pictures
of microtubule structure and cell damage, but there is a major difference
in their effect on cell lines showing multiple drug resistance; epothilones
are between about 2000 and 5000 times more active than paclitaxel in these
experiments. Their important antitumor activity combined with their relative
structural simplicity compared to that of paclitaxel and a much better
water solubility of the epothilones define exciting opportunities for synthetic
chemists, biologistst, and clinicians with regard to the development of
a powerful new anti-cancer drug. Due to their impressive biological profile,
several groups engaged in synthetic organic and natural products chemistry
focused their efforts on developing strategies for the total synthesis
of epothilones and their synthetic analogues. Suggested reading: D. Schinzer,
A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2,
1477; D. Schinzer, A. Limberg, A. Bauer. O. M. Böhm, M. Cordes, Angew.
Chem. 1997, 109, 545; D. Schinzer, A. Limberg, Scientific
American/ Spektrum der Wissenschaft 1997, August issue,
page 38; D. Schinzer, A. Bauer, J. Schieber, Synlett 1998,
861; D. Schinzer, A. Bauer Science Spectra, 1999, 18,
64; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, Chem.
Eur. J. 1999, 2483; D. Schinzer, A. Bauer, J. Schieber, Chem.
Eur. J. 1999, 2492.
|
| Receptor Studies |
| Interactions of biologically active small molecules with biopolymers
(DFG collaboration with Prof. Griesinger, University of Frankfurt/Main).
13C-labled epothilones are studied in polymerization experiments with tubulin.
These studies are designed to gain information about the reactive conformation
of epothilone at the biological receptor.
|
| Design of Anti-Tumor
Active Agents |
| EU Network "Design and Synthesis of Novel Paclitaxel (Taxol®) Mimics
Using a Common Pharmacophore Model for Microtubule-Stabilising Anticancer
Agents"; Improving Human Potential [IHP] Programme of the European Union,
Proposal RTN1-1999-00129.
|
| Sorangicines |
| In a very recent total synthesis project we have focussed on the total
synthesis of sorangicin A, a very potent antibiotic agent, isolated from
myxo bacteria (see picture). The required building blocks have already
been synthesized. Of particular interest is the the unsual bicyclic ether
subunit, which was only found in one other natural product (palytoxin).
Research projects are under way to couple the strategic intermediates.
Suggested reading: in preparation.
|
| Cephalotaxine |
| In recent studies we have shown that the Beckmann rearrangement can
be combined with an allylsilane cyclization to form various heterocyclic
systems by way of a tandem reaction. We have focused on the synthesis of
tricyclic 7- and 8-membered ring systems that are important skeletons in
a number of pharmacologically important natural and unnatural products.
In particular the antitumor-active ester derivatives of the pentacyclic natural product cephalotaxine (isolated from Cephalotaxus, see picture) attracted our attention. Suggested reading: D.Schinzer und Yunxin Bo, Angew.Chem. 1991, 103, 727; D. Schinzer, E. Langkopf, Synlett 1994, 375; ", D. Schinzer, U. Abel, Synlett 1997, 632. |
| For
a nice picture of our target molecules click |
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