Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold

Altmann, Karl-Heinz; Cachoux, Frédéric; Feyen, Fabian; Gertsch, Jürg; Kuzniewski, Christian N; Wartmann, Markus (2010). Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold. CHIMIA, 64(1-2), pp. 8-13. Bern: Schweizerische Chemische Gesellschaft 10.2533/chimia.2010.8

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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 macro-lactones, 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'.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gertsch, Jürg

ISSN:

0009-4293

Publisher:

Schweizerische Chemische Gesellschaft

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:12

Last Modified:

17 Mar 2015 19:14

Publisher DOI:

10.2533/chimia.2010.8

PubMed ID:

21137676

Web of Science ID:

000275291600002

URI:

https://boris.unibe.ch/id/eprint/2433 (FactScience: 204932)

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