Entwicklung neuartiger Zytostatika für eine selektive Krebstherapie

• Applicant: Professor Dr. Lutz F. Tietze
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2007 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35715300

• Final Report Year: 2011

Final Report Abstract

We have developed novel glycosidic prodrugs within our research project on the development of novel anticancer agents for a selective treatment of malignant tumors, which was supported by the DFG. The compounds are based on the natural antibiotics CC-1065 and duocarmycin SA and will be used in the antibody directed enzyme prodrug therapy concept (ADEPT), which in a binary approach uses conjugates of monoclonal antibodies, that bind to tumor associated antigens, and an enzyme as well as a comparable little toxic prodrug. The best results were achieved with compounds containing two pharmacophoric units, which were connected with a dicarboxylic acid. These compounds show an astonishing high cytotoxicity with an IC50 value of 110 fM. On the other hand they can be detoxified by the factor 106 by introducing two sugar molecules. The sugars can be removed by the antibody-enzyme conjugate in the cancer tissue restoring the high cytotoxicity of the drug. The results are so far world leading. In addition, we have investigated the mode of action of our analogs showing for the first time that there is a second target for the compounds derived from duocarmycin and CC-1065 and probably also for the natural antibiotics themselves. The target is an aldehyddehydrogenase, which presumably is the only target for the binary structures without the DNA-binding unit.

Publications

• Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC-1065 and the Duocarmycins. Chemistry - A European Journal, Vol. 13. 2007, Issue 16, pp. 4396–4409.
  L.F. Tietze, F. Major, I. Schuberth, D.A. Spiegl, B. Krewer, K. Maksimenka, G. Bringmann, J. Magull
  
• Duocarmycin Based Prodrugs for Cancer Prodrug-Monotherapy. Bioorganic & Medicinal Chemistry, Vol. 16. 2008, Issue 12, pp. 6312–6318.
  L.F. Tietze, H.J. Schuster, K. Schmuck, I. Schuberth, F. Alves
  
• Enantio- and Diastereoselective Synthesis of Duocarmycine-Based Prodrugs for a Selective Treatment of Cancer by Epoxide Opening. Chemistry - A European Journal, Vol. 14. 2008, Issue 3, pp. 895–901.
  L.F. Tietze, H.J. Schuster, S.M. Hampel, S. Rühl, R. Pfoh
  
• Synthesis and Biological Evaluation of a Novel Pentagastrin-Toxin Conjugate Designed for a Targeted Prodrug Monotherapy of Cancer. International Journal of Molecular Sciences, Vol. 9. 2008, Issue 5, pp. 821-837.
  L.F. Tietze, O. Panknin, B. Krewer, F. Major, I. Schuberth
  
• Synthesis of a Novel Pentagastrin-Drug Conjugate for a Targeted Tumor Therapy. Chemistry - A European Journal, Vol. 14. 2008, Issue 9, pp. 2811–2818.
  L.F. Tietze, O. Panknin, F. Major, B. Krewer
  
• Antibody-Directed Enzyme Prodrug Therapy: A Promising Approach for a Selective Treatment of Cancer Based on Prodrugs and Monoclonal Antibodies. Chemical Biology & Drug Design, Vol. 74. 2009, Issue 3, pp. 205–211.
  L.F. Tietze, B. Krewer
  
• CD-spectroscopy as a powerful tool for investigating the mode of action of unmodified drugs in live cells. Journal of the American Chemical Society (JACS), Vol. 131. 2009, Issue 36, pp. 13031–13036.
  L.F. Tietze, B. Krewer, F. Major, I. Schuberth
  
• Concept of a selective tumour therapy and its evaluation by near-infrared fluorescence imaging and flat-panel volume computed tomography in mice. European Journal of Radiology, Vol. 70. 2009, Issue 2, pp. 286–293.
  F. Alves, C. Dullin, J. Napp, J. Missbach-Guentner, K. Jannasch, J. Mathejczyk, L.A. Pardo, W. Stühmer, L.F. Tietze
  
• Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065. Toxins, Vol. 1. 2009, Issue 2, pp. 134-150.
  L.F. Tietze, B. Krewer, J.M. von Hof, H. Frauendorf, I. Schuberth
  
• Probing the mechanism of action of potential anticancer agents at a molecular level using electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry. European Journal of Mass Spectrometry, Vol. 15. 2009, Issue 5, pp. 661–672.
  L.F. Tietze, B. Krewer, H. Frauendorf
  
• Atropisomerism of Aromatic Carbamates. Chemistry - A European Journal, Vol. 16. 2010 , Issue 42, pp. 12678–12682.
  L.F. Tietze, H.J. Schuster, J.M. von Hof, S.M. Hampel, J.F. Colunga, M. John
  
• Glycosidic Prodrugs of Highly Potent Bifunctional Duocarmycin Derivatives for Selective Treatment of Cancer. Angew. Chem. 2010, 122, 7494-7497. Angewandte Chemie International Edition, Vol. 49. 2010, Issue 40, pp. 7336–7339.
  L.F. Tietze, J.M. von Hof, M. Müller, B. Krewer, I. Schuberth
  
• Synthesis of Fluorescence Labeled Glycosidic Prodrugs Based on the Cytotoxic Antibiotic Duocarmycin. European Journal of Organic Chemistry, Vol. 2010, Issue 36, pp. 6909–6921.
  L.F. Tietze, F. Behrendt, F. Major, B. Krewer, J.M. von Hof
  
• Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity. Organic & Biomolecular Chemistry Vol. 8. 2010,Issue 8, pp. 1833-1842.
  H.J. Schuster, B. Krewer, J.M. von Hof, K. Schmuck, I. Schuberth, F. Alves, L.F. Tietze
  
• Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA. Cancer Gene Therapy, Vol. 18. 2011, pp. 42-52.
  C.M. Seubert, J. Stritzker, U. Donat, J.B. Sturm, N. Chen, J.M. von Hof, B. Krewer, L.F. Tietze, I. Gentschev, A.A. Szalay
  
• SiFA Azide - A New Building Block for PET Imaging Using Click Chemistry. Synlett, Vol. 12. 2011, pp. 1697-1700.
  L.F. Tietze, K. Schmuck
  
• Spectroscopically Well-Characterized RGD Optical Probe as a Prerequisite for Lifetime-Gated Tumor Imaging. Molecular Imaging, Vol. 10. 2011, Issue 6, pp. 469-480.
  J.E. Mathejczyk, J. Pauli, C. Dullin, J. Napp, L.F. Tietze, H. Kessler, U. Resch-Genger, F. Alves
  
• Synthesis and Biological Evaluation of Prodrugs Based on the Natural Antibiotic Duocarmycin for Use in ADEPT and PMT. Chemistry - A European Journal, Vol. 17. 2011, Issue 6, pp. 1922–1929.
  L.F. Tietze, K. Schmuck, H.J. Schuster, M. Müller, I. Schuberth