Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold

Authors

  • Karl-Heinz Altmann Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, ETH Hönggerberg, HCI H 405, CH-8093 Zürich;, Email: karl-heinz.altmann@pharma.ethz.ch
  • Frédéric Cachoux University of Bern, Institute of Biochemistry and Molecular Medicine, CH-3012 Bern
  • Fabian Feyen Carbogen-Amcis AG, CH-5502, Hunzenschwil
  • Jürg Gertsch Pierre Fabre Research Center, F-81106 Castres Cedex, France
  • Christian N. Kuzniewski Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, ETH Hönggerberg, HCI H 405, CH-8093 Zürich
  • Markus Wartmann Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel

DOI:

https://doi.org/10.2533/chimia.2010.8

Keywords:

Anticancer, Azathilones, Drug discovery, Epothilones, Natural product synthesis

Abstract

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macrolactones, whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'.

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Published

2010-02-26

How to Cite

[1]
K.-H. Altmann, F. Cachoux, F. Feyen, J. Gertsch, C. N. Kuzniewski, M. Wartmann, Chimia 2010, 64, 8, DOI: 10.2533/chimia.2010.8.