Thomas Schrader, Ph.D. University of Duisburg-Essen Essen, Germany
Thomas Schrader studied Chemistry at Bonn University, Germany and received his Ph.D. (Dr. rer. nat.) in 1988 (new synthetic avenues towards aminophosphonic acids, W. Steglich). After a postdoctorate at Princeton University (U.S.A.) under the guidance of E. C. Taylor (total synthesis of antitumor agents based on C-analogs of tetrahydrofolic acid), he moved to Düsseldorf University to begin his own research associated to the group of G. Wulff. Habilitation and venia legendi in Organic Chemistry were achieved in 1998 on a topic, which combined asymmetric synthesis with supramolecular chemistry. Dr. Schrader was subsequently called to Marburg University (2000), where he served as Associate Professor; here he developed new artificial receptors for small biomolecules. In 2006, he moved to Essen, where he now holds a chair in Organic Chemistry. Since April 2014, he is also speaker of the new DFG Collaborative Research Centre 1093 “Supramolecular Chemistry on Proteins”. His research aims at gaining control over biological functions by rationally designed synthetic receptor molecules. This fundamental research applies principles from supramolecular chemistry to the targeting and manipulation of proteins, nucleic acids and lipids, by external designed molecular agents. Together with Dr. Klärner, he discovered the extraordinary potential of water-soluble molecular clips and tweezers for protein and cofactor recognition. Homepage: https://www.uni-due.de/chemie/ak_schrader/index_en
Molecular Tweezers and Clips
The molecular tweezers and clips (Figure 1) possess a torus-shaped or central parallel cavity with a surrounding belt of convergent aromatic rings; hence these structures exploit multiple aromatic interactions in a positively cooperative manner. Both tweezers and clips show selective binding of cationic or neutral guest molecules that bear electron-withdrawing groups.1
R = H, OH, OAc, OMe (water-insoluble); R = OPO32- 2M+, OP(Me)O2– M+, OSO3– M+ (M+ = Na+, Li+: water-soluble)
Figure 1. Structures of the molecular tweezers (spaced by a central benzene or naphthalene bridge) and molecular clips having naphthalene or anthracene side walls.
The electrostatic surface potentials (ESP) explain this unexpected behavior: calculated ESPs are highly negative inside the tweezer or clip cavity, providing complementary profiles to the positive ESP plots of their preferred guest molecules (Figure 2).2
Figure 2. Electrostatic surface potential calculated by PM3 for BenzTW (R = OPO32– 2Li+, top left), NaphCL (R = OPO32– 2Li+, top right), AcLysOMe•HCl (bottom left), and NAD+ (bottom right). The color code spans from -25 kcal/mol (red) to +25 kcal/mol (blue).
Frank-Gerrit Klärner, Ph.D. University of Duisburg-Essen Essen, Germany
Frank-Gerrit Klärner studied chemistry at the University of Köln (Cologne, Germany) and received his Ph.D. (Dr. rer. nat) there for work in the field of arene oxides and oxepines in the laboratory of Professor Emanuel Vogel in 1968. In 1974 he finished his “Habilitation” at the Ruhr-University of Bochum, was associate professor in Bochum from 1980-1992, and visiting professor at the University of Wisconsin, Madison, USA in 1983. Since 1992 he has been full professor at the University of Duisburg-Essen, chaired the DFG center of supramolecular research at the Universities in Essen and Bochum (DFG – German Funding Agency) from 1998-2005 and retired in 2006. His research interests have been in the fields of pericyclic reactions (sigmatropic rearrangements and cyloadditions), high-pressure chemistry (up to 14 kbar), and supramolecular chemistry (design and synthesis of molecular tweezers and clips). The tweezers and clips serve as synthetic host molecules for electron-poor aliphatic and/or aromatic guest molecules. Water-soluble tweezers and clips (synthesized and investigated in collaboration with Professor Thomas Schader) bind to bioactive chemical compounds selectively, for example to the basic amino acids lysine or arginine and enzyme cofactors NAD(P)+, respectively. They inhibit certain enzymatic reactions and aberrant protein aggregations. Molecular mechanics and quantum chemical calculations are employed for the understanding of these higher organized systems. Homepage: http://www.orgchem.uni-essen.de/ak-klaerner/ak_klaerner.htm
1. F.-G. Klärner, J. Benkhoff, R. Boese, U. Burkert, M. Kamieth, U. Naatz, Angew. Chem. Int. Ed. Engl. 1996, 35, 1130-1133. Molecular Tweezers as Synthetic Receptors in Host-Guest Chemistry: Inclusion of Cyclohexane and Self-Assembly of Aliphatic Side Chains; F.-G. Klärner, U. Burkert, M. Kamieth, R. Boese, and J. Benet-Buchholz, Chem. Eur. J. 1999, 5, 1700-1707. Molecular Tweezers as Synthetic Receptors: Molecular Recognition of Electron-Deficient Aromatic and Aliphatic Substrates; F.–G. Klärner, J. Panitzky, D. Bläser, R. Boese, Tetrahedron 2001, 3673 – 3687. Syntheses and Supramolecular Structures of Molecular Clips; review: F.-G. Klärner, B. Kahlert Acc. Chem. Res. 2003, 36, 919-932. Molecular tweezers and clips as synthetic receptors. Molecular recognition and dynamics in receptor-substrate complexes.
2. M. Kamieth, F.-G. Klärner, F. Diederich, Angew. Chem. Int. Ed. 1998, 37, 3303-3306. Modeling the Supramolecular Properties of Aliphatic-Aromatic Hydrocarbons with Convex-Concave Topology; F.-G. Klärner, J. Panitzky, D. Preda, L.T. Scott, J. Mol. Model. 2000, 6, 318-327. Modeling of Supramolecular Properties of Molecular Tweezers, Clips, and Bowls.
4. F.-G. Klärner, B. Kahlert, A. Nellesen, J. Zienau, C. Ochsenfeld, T. Schrader, J. Am. Chem. Soc. 2006, 128, 4831-4841, J. Am. Chem. Soc. 2010, 132, 4029. Molecular tweezer and clip in aqueous solution: Unexpected self-assembly, powerful host-guest complex formation, quantum chemical H-1 NMR shift calculation.
5. C. Jasper, T. Schrader, J. Panitzky, F.-G. Klärner, Angew. Chem. Int. Ed. 2002, 41, 1355-1358, Selective Complexation of N-Alkylpyridinium Salts: Recognition of NAD+ in Water; M. Fokkens, C. Jasper C, T. Schrader, F. Koziol, C. Ochsenfeld, J. Polkowska, M. Lobert, B. Kahlert, F.-G. Klärner, Chem. Eur. J. 2005, 11, 477-494. Selective complexation of N-alkylpyridinium salts: binding of NAD+ in water; J. Polkowska, F. Bastkowski, T. Schrader, F.-G. Klärner, J. Zienau, F. Koziol, C. Ochsenfeld, J. Phys. Org. Chem. 2009, 22, 779–790. A combined experimental and theoretical study of the pH-dependent binding mode of NAD+ by water-soluble molecular clips.
6. M Fokkens, T. Schrader, F.-G. Klärner, J. Am. Chem. Soc. 2005, 127, 14415-14421. A molecular tweezer for lysine and arginine; S. Dutt, C. Wilch, T. Gersthagen, P. Talbiersky, K. Bravo-Rodriguez, M. Hanni, E. Sánchez-García,C. Ochsenfeld, F.-G. Klärner, T. Schrader, J. Org. Chem., 2013, 78 (13), 6721–6734, Molecular Tweezers with Varying Anions – A Comparative Study.
8. M. Kirsch, P. Talbiersky, J. Polkowska, F. Bastkowski, T. Schaller, H. de Groot, F.-G. Klärner, T. Schrader, Angew. Chem. Int. Ed. 2009, 48, 2886-2890, A Mechanism of Efficient G6PD Inhibition by a Molecular Clip.
9. D. Bier, R. Rose, K. Bravo-Rodriguez, M. Bartel, J. M. Ramirez-Anguita, S. Dutt, C. Wilch, F.-G. Klärner, E. Sanchez-Garcia, T. Schrader, C. Ottmann,Nature Chemistry2013, 5, 234–239, Molecular tweezers modulate 14-3-3 protein–protein interactions.
10. S. Sinha, D. H. J. Lopes, Z. Du, E. S. Pang, A. Shanmugam, A. Lomakin, P. Talbiersky, A. Tennstaedt, K. McDaniel, R. Bakshi, P.-Y. Kuo, M. Ehrmann, G. B. Benedek, J. A. Loo, F.-G. Klärner, T. Schrader, C. Wang, G. Bitan, J. Am. Chem. Soc. 2011, 133, 16958–16969. Lysine-Specific Molecular Tweezers are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins. S. Prabhudesai, S. Sinha, A. Attar, A. Kotagiri, A. G. Fitzmaurice, R. Lakshmanan, M. I. Ivanova, J. A. Loo, F.-G. Klärner, T. Schrader, M. Stahl, G. Bitan, J. M. Bronstein, Neurotherapeutics 2012, 9, 464-476. A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo.S. Sinha, Z. Du, P. Maiti, F.–G. Klärner, T. Schrader,C. Wang, G. Bitan, ACS Chem. Neurosci. 2012, 3(6), 451–458. Comparison of Three Amyloid Assembly Inhibitors: The Sugar scyllo-Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01. A. Attar, C. Ripoli, E. Riccardi, P. Maiti, D. D. Li Puma, T. Liu, J. Hayes, M. R. Jones, K. Lichti-Kaiser, F. Yang, G. D. Gale, C. Tseng, M. Tan, C.-W. Xie, J. L. Straudinger, F.-G. Klärner, T. Schrader, S. A. Frautschy, C. Grassi, G. Bitan, Brain2012: 135, 3735–3748, Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers.