Biomimetic Surface Engineering
The selective functionalization of bone and metal surfaces is attractive for various applications in implantation medicine and bone engineering. The formation of biofilms on implants, for example, is a serious clinical problem leading to inflammation and eventually rejection of the implant. This biofouling can be prevented by the attachment of macromolecules such as polyethylenglycol or antiobiotics to the implant surface. On the other hand, functionalization of the implant materials with cell-adhesives like the RGD tripeptide can lead to improved adhesion to native tissues. We have developed multivalent scaffolds, resembling the tripodal structure of natural siderophores and mussel adhesion proteins. These scaffolds are modular and may be conjugated to known surface binders such as catecholates (eg dopamine for metal binding) and bisphosphonates (eg pamidronate for bone binding). The resulting conjugates are immobilized on titanium or bone surfaces respectively via a dip-and-rinse procedure. Attachment of various biological effector molecules such as antibiotics, peptides or carbohydrates are performed by a bioorthogonal ‘’click-reaction’’ enabling the dedicated tailoring of surface properties.
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- Zurcher, S.; Wackerlin, D.; Bethuel, Y.; Malisova, B.; Textor, M.; Tosatti, S.: Gademann, K. J. Am. Chem. Soc. 2006, 128, 1064.
- Franzmann, E.; Khalil, F.; Weidmann, C.; Schröder, M.; Rohnke, M.; Janek, J.; Smarsly, B. M.; Maison, W. Chem. -- Eur. J. 2011, 17, 8596.
The selective recognition of carbohydrates under physiological conditions is one of the biggest challenges of chemical biology. In this context, boronic acids are among the most promising candidates for specific recognition of carbohydrates in water.3 However, this approach has severe limitations: most boronic acids have not yet been demonstrated to bind to nonreducing sugars and glycosides, which account for the large majority of oligosaccharides found in the form of cell-surface glycoconjugates. Moreover, many of the currently established standard boronic acids for the recognition of simple carbohydrates tend to have limited solubility in aqueous solutions. Notable exceptions are ortho-functionalized phenylboronic acids, which have been shown recently to bind glycosidic structures selectively.For the detection of pathogen and cancer specific cell surface proteoglycanes, we use fuctionalized phenylboronates to overcome the above mentioned drawbacks and make them amenable to pathogen and tumor targeting. We make use of multivalency effects to increase the affinity of our carbohydrate binders and assemble them in an appropriate geometry to recognize cell surface glycotopes. In this context we have developed mimetics of C3-symmetric lectines and are thus following a biomimetic concept for carbohydrate recognition.
- James, T. D.; Phillips, M. D.; Shinkai, S. Boronic acids in saccharide recognition; RSC Publishing: Cambridge, UK, 2006.
- Dowlut, M.; Hall, D. G. J. Am. Chem. Soc. 2006, 128, 4226.
- Zou, Y. J.; Broughton, D. L.; Bicker, K. L.; Thompson, P. R.; Lavigne, J. J. Chembiochem 2007, 8, 2048.
- Wienhold, F.; Claes, D.; Graczyk, K.; Maison, W. Synthesis 2011, 4059.
Enzymatic allylic oxidations of terpenoides
Allylic oxidations belong to the most attractive synthetic transformations because they convert readily available and cheap starting materials into value-added products. In this study, we describe oxidative conversions of terpenoides and a number of related cycloalkenes with a lyophilisate of the edible fungus Pleurotus sapidus. The biocatalytic protocol is simple and the biocatalyst is readily available. The conversions of various cycloalkenes proceed cleanly in most cases to the corresponding enones. The substrate scope is remarkable and includes a number of mono- and sequiterpenes, functionalized terpenoides as well as simple cyclohexenes and benzylic substrates. Enzymatic allylic oxidations by Pleurotus sapidus are thus an excellent non-toxic alternative to metal-mediated oxidation procedures in academic labs and for industrial application in food technology, cosmetics or pharmaceutical research.
Traditionally, chromium based oxidants have been used for conversions of olefins to enones and excellent stoichiometric and catalytic protocols have been developed by Muzard and many other groups. However, from an economical and ecological point of view it is still desirable to compliment these metal-catalysed variants with biocatalytic approaches. In this context, a number of microorganisms or fungi are able to oxidize terpenoides, which are attractive substrates for many flavour compounds. A good example is the selective and efficient allylic oxidation of the sesquiterpene (+)-valencene 4 to the grapefruit flavour compound (+)-nootkatone 5 that was achieved with the edible fungus Pleurotus sapidus (PSA). Particularly toxicity issues make the use of edible fungi attractive compared to other biocatalytic systems like bacteria or yeasts: They are nontoxic and for this reason their application in food, pharmaceutical and cosmetic industry is simple and safe. It should be noted that biocatalytic oxidations with PSA may be performed with the lyophilisate of the fungus. The required biocatalytic systems are thus readily available even for synthetic laboratories without microbiological expertise. The catalytically active lyophilisate may be obtained in any desired amount by freeze drying of the fungal fruiting bodies, which are commercially available or and may be grown in submerged cultures.
In cooperation with Prof. Dr. Holger Zorn, we are evaluating the synthetic potential of PSA lyophilisates for the chemoselective oxidation of terpenoides and other readily available alkenes.
- Rickert, A.; Krombach, V.; Hamers, O.; Zorn, H.; Maison, W. Green Chem. 2012, DOI: 10.1039/C2GC16317A.
- J. Muzart, Mini-Rev. Org. Chem., 2009, 6, 9.
- M. A. Fraatz, S. J. L. Riemer, R. Stöber, R. Kaspera, M. Nimtz, R. G. Berger and H. Zorn, J. Mol. Catal. B: Enzym., 2009, 61, 202.
Synthesis of spirooxindole natural products
Spirocyclic structures are abundant in many natural products and have always been a challenge for synthetic organic chemists. In particular the 3,3’-pyrrolidinyl-spirooxindoles constitute a pharmaceutically valuable class of biologically active compounds, which can be isolated from plants and fungi. These natural products have a fascinating architecture and various biological activities such as anticancer properties, contraceptive action and anti-migraine activity have been reported. The 3,3’-pyrrolidinyl-spirooxindole scaffold is therefore a privileged structural element with respect to pharmaceutical applications.
We have applied the intramolecular Pd-catalyzed alpha-arylation of anilides to the synthesis of 3,3’-pyrrolidinyl-spirooxindoles. The [Pd]-PEPPSI-catalyst system was found to be the best choice for conversion of functionalized heterocyclic derivatives. The methodology is valuable for the synthesis of spirooxindole natural products as has been demonstrated with the synthesis of the natural spirooxindoles horsfiline and coerulescine. More complex spirooxindoles should also be accessible and these applications are under investigation.
- Deppermann, N.; Thomanek, H.; Prenzel, A. H. G. P.; Maison, W., J. Org. Chem. 2010, 75, 5994.
- Deppermann, N.; Prenzel, A. H. G. P.; Beitat, A.; Maison, W., J. Org. Chem. 2009, 74, 4267.
One of the major challenges in current cancer therapy is the sensitive detection of small tumours. None of the known methods is sufficiently precise for high resolution cancer imaging. In this context, cancer specific receptors, which are over expressed ideally on the surface of cancer cells, have attracted considerable attention as tumour markers. If conjugated to contrast reagents or dyes, ligands for cancer specific receptors can guide marker moieties to a tumour site and allow the sensitive detection of cancer. We have developed new biomimetic multivalent platforms for prostate tumour targeting based on rigid scaffolds. The design of these platforms has been inspired by natural polyvalent cell surface binders such as antibodies and lectins and lead us to design fundamentally new rigid scaffolds based on adamantane. These scaffolds improve the pharmacokinetics and binding characteristics of low molecular weight ligands for cancer specific membrane antigens like PSMA (prostate specific membrane antigen) and members of the TNFR-family (tumor necrosis factor receptor).
In cooperation with Prof. John V. Frangioni (Harvard Medical School, Cambridge USA) and Dr. Gilles Guichard (IECB, Bordeaux France) we are working on the development of cancer specific diagnostics for NIR-, SPECT- and PET-imaging and novel cancer therapeutics.
- W. Maison, J. V. Frangioni, N. Pannier, Org. Lett. 2004, 6, 4567-4569.
- V. Pavet, J. Beyrath, C. Pardin, A. Morizot, M.-C. Lechner, J.-P. Briand, M. Wendland, W. Maison, S. Fournel, O. Micheau, G. Guichard, H. Gronemeyer, Cancer Res. 2010, 70, 1101.
- V. Humblet, P. Misra, K. R. Bushan, Y.-S. Ko, T. Tsukamoto, N. Pannier, J. V. Frangioni, W. Maison, J. Med. Chem. 2009, 52, 544.
- P. Misra, V. Humblet, N. Pannier, W. Maison, J. V. Frangioni, J. Nucl. Med. 2007, 48, 1379.