Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold
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 clinic...
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| Format: | Article |
| Language: | deu |
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Swiss Chemical Society
2010-02-01
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| Series: | CHIMIA |
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| Online Access: | https://www.chimia.ch/chimia/article/view/4789 |
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| author | Karl-Heinz Altmann Frédéric Cachoux Fabian Feyen Jürg Gertsch Christian N. Kuzniewski Markus Wartmann |
| author_facet | Karl-Heinz Altmann Frédéric Cachoux Fabian Feyen Jürg Gertsch Christian N. Kuzniewski Markus Wartmann |
| author_sort | Karl-Heinz Altmann |
| collection | DOAJ |
| description |
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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| first_indexed | 2024-12-24T00:16:54Z |
| format | Article |
| id | doaj.art-8768fba7639648829d95c17e1b19899f |
| institution | Directory Open Access Journal |
| issn | 0009-4293 2673-2424 |
| language | deu |
| last_indexed | 2024-12-24T00:16:54Z |
| publishDate | 2010-02-01 |
| publisher | Swiss Chemical Society |
| record_format | Article |
| series | CHIMIA |
| spelling | doaj.art-8768fba7639648829d95c17e1b19899f2022-12-21T17:24:42ZdeuSwiss Chemical SocietyCHIMIA0009-42932673-24242010-02-01641-210.2533/chimia.2010.8Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone ScaffoldKarl-Heinz Altmann0Frédéric Cachoux1Fabian Feyen2Jürg Gertsch3Christian N. Kuzniewski4Markus Wartmann5Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, ETH Hönggerberg, HCI H 405, CH-8093 Zürich;, Email: karl-heinz.altmann@pharma.ethz.chUniversity of Bern, Institute of Biochemistry and Molecular Medicine, CH-3012 BernCarbogen-Amcis AG, CH-5502, HunzenschwilPierre Fabre Research Center, F-81106 Castres Cedex, FranceSwiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, ETH Hönggerberg, HCI H 405, CH-8093 ZürichNovartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel 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'. https://www.chimia.ch/chimia/article/view/4789AnticancerAzathilonesDrug discoveryEpothilonesNatural product synthesis |
| spellingShingle | Karl-Heinz Altmann Frédéric Cachoux Fabian Feyen Jürg Gertsch Christian N. Kuzniewski Markus Wartmann Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold CHIMIA Anticancer Azathilones Drug discovery Epothilones Natural product synthesis |
| title | Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold |
| title_full | Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold |
| title_fullStr | Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold |
| title_full_unstemmed | Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold |
| title_short | Natural Products as Leads for Anticancer Drug Discovery: Discovery of New Chemotypes of Microtubule Stabilizers through Reengineering of the Epothilone Scaffold |
| title_sort | natural products as leads for anticancer drug discovery discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold |
| topic | Anticancer Azathilones Drug discovery Epothilones Natural product synthesis |
| url | https://www.chimia.ch/chimia/article/view/4789 |
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