Schlüsselwörter
(Englisch)
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total synthesis; cancer; cyclization reactions; natural products; chemical biology
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Forschungsprogramme
(Englisch)
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COST-Action CM0804 - Chemical Biology with Natural Products
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Kurzbeschreibung
(Englisch)
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Modifications of the recently synthesized gonioma alkaloid goniomitine and total synthesis of the anticancer aspidosperma alkaloid jerantinines are proposed. Study of their bioactivity and structure activity relationships will allow the synthesis of more potent analogs with potential application in anticancer therapy.
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Weitere Hinweise und Angaben
(Englisch)
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Full name of research-institution/enterprise: EPF Lausanne SB ISIC LCSO Laboratory of Catalysis and Organic Synthesis (LCSO)
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Partner und Internationale Organisationen
(Englisch)
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BE, CH, CZ, DE, DK, EL, ES, FI, FR, IE, IT, LT, LV, NO, PT, RO, RS, SE, TR, UK
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Abstract
(Englisch)
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Small organic molecules play a key role for the development of new cure against life-threatening diseases, like cancer, in two respects: as lead compounds for the development of new drugs and as chemical tools to better understand biological systems. Natural products, such as taxol or the vinca alkaloids, have taken center stage as either the source of anticancer compounds, or function as structural inspiration in the development of potent natural product-like analogs to battle this devestating desease. However, efficient methods to synthesize such anticancer agents continue to be non-trivial due to the high-degree of structural complexity exhibited by these natural products. Consequently, organic chemists are challenged to develop novel and improved methodologies to access these complex molecules in an efficient manner. In this context, we have recently developed selective cyclizations of amino cyclopropanes as a highly efficient entry into the core of the aspidosperma and gonioma alkaloids. Utilizing this powerful methodology as key transformation, we were able to accomplish the total synthesis of the aspidosperma alkaloid jerantinine E. Recently isolated from the Malayan Tabernaemontana corymbosa, jerantinine E shows intersting and promising bioactivity against different cancer cell-lines. Our chemical synthesis allowed for the first time to access larger amounts of the natural products, which allowed our collaborators to carry in-depth biological studies and identify tubulin as the biological target of jerantinine E. Furthermore, the natural product was found to display significant activity against several human cancer-cell lines and to efficiently inhibit the migration of tumor cells, which is important to prevent the formation of metastasis. In a second part of the project, focus was moved from synthesis to the functionalization of bioactive molecules. The availability of practical functionalization methods for complex drugs and biomolecules will lead to improved drug-like properties and the synthesis of important bioconjugates for the study of the biology of the cell. More specifically, a very efficient method for the transfer of alkynes to aliphatic, aromatic and peptidic compounds was developed. The rich chemistry of alkynes, especially in the case of bioconjugation via cycloaddition reactions will set the basis for the synthesis of fine-tuned drugs and smart molecules for the study of the cell.
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Datenbankreferenzen
(Englisch)
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C10.0116
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