Synthesis and mode of action studies of spirocyclic alkaloids
Project type
PhD
| Supervisor(s) | Division | |
| (Primary) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
Details of project
Our laboratory has an interest in natural cyclic guanidine compounds. We successfully synthesised Naamidine A, a known inhibitor of tumour growth, via an efficient route (1). This work has allowed preliminary biological studies to be conducted at the Ludwig Institute of Cancer Research to understand its mode of action.
Although the actual protein with which Naamidine A interacts has not yet been discovered, the list of possible targets has been narrowed down significantly. At the same time, we are interested in preparing other cyclic guanidine alkaloids derived from Naamidine A, in particular Spiroleucettadine that shows potent antibiotic activity. The actual structure of Spiroleucettadine has not been confirmed yet and there are no reported syntheses of this unique molecule. We and others have proposed corrected structures, explaining the difficulty encountered in performing the final stages of the synthesis of the original proposed molecule (2, 3, 4).
This PhD project aims at exploring synthetic routes towards the two revised structures of spiroleucettadine via a biosynthetic pathway. In collaboration with the proteomics group of the Institute, we will aim at elucidating the target of both Naamidine A and Spiroleucettadine. The candidate should have a strong interest in projects involving multidisciplinary approaches and a willingness to work at the interface of chemistry and biology. A strong background in organic synthesis is encouraged.
Project references
- Aberle NS, Lessene G, Watson KG. A concise total synthesis of naamidine A. Org Lett. 2006 Feb 2;8(3):419-21 PMID: 16435849
- Li C and Danishefsky SJ. Studies directed toward the synthesis of the guanidine alkaloid, spiroleucettadine: some observations at the level of structure. Tetrahedron Letters. 2006 47(3):385-387.
- Chang JJ, Chan B and Ciufolini MA. Synthetic Studies Toward Spiroleucettadine. Tetrahedron Letters. 2006 47:359-3601.
- Aberle N, Ovenden SPB, Lessene G, Watson KG and Smith BJ. Spiroleucettadine: synthetic studies and investigations towards structural revision. Tetrahedron Lett. 2007 48:2199.
Research interests
Our laboratory is interested in using chemical approaches to elucidate biological pathways. Using efficient synthetic methodologies, we aim at preparing molecules with defined biological activity. We have strong interactions with a number of other divisions at the institute with which we collaborate. We participate in key areas of biomedical research (e.g. apoptosis, cancer, etc.) by providing chemical probes, which can be used in parallel to genetic an biological approaches. Our interest in biologically active molecules extends to natural products. Because of their unique structures and often interesting biological activities, these compounds represents attractive targets for medicinal chemistry.
Research theme
Cancer
Scientific discipline
- Chemistry
- Medicinal Chemistry
Keywords
Natural product synthesis, elucidation of mechanism of action