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Content archived on 2024-05-29

Synthesis of Eleutheside Analogues : Potential Microtubule-Stabilizing Anticancer Drugs

Objective

Cancer continues to be an important public health concern and socio-economic problem. Among the most promising newly established drugs, palliate (Taxi) and docetaxel (Texture) have the broadest ant tumour spectra in the clinic and are used increasingly for the treatment of ovarian cancer and metastasis breast cancer, with promise also for the treatment of lung, skin, and head and neck cancers. However, this beneficial effect still remains hampered by many drawbacks. The major cellular target for palliate and other taxies is the protein tubule, whose polymerisation into microtubules is induced and stabilised, blocking the tumour cells in mitosis and preventing proliferation. Recently, several natural products isolated both from marine sources (soft corals or sponges) and from terrestrial bacteria have been reported to exert potent catatonic activity through a related-related mechanism. Among these, sarcodictyins A and B and eleutherobin (the " eleutheside" family of microtubule- stabilizing agents) are active against paclitaxel-resislant tumour cell lines and therefore hold potential as second generation microtubule-stabilizing anticancer drugs. Given the scarcity of the natural products, a practical total synthesis of the eleuthesides (amenable to large-scale preparation at a reasonable cost), and the synthesis of simplified eleutheside analogues, are still strongly desirable. The central aim of this project is to use the expertise gained within the group in the preparation of tri- substituted eleutheside analogues, and attempt the synthesis of: (a) a number of new eleutheside analogues functionalized at C-7; (b) the fully functionalised analogues, from which the Danishes key-intermediate (an advanced intermediate in the total synthesis of eleutherobin) could be easily obtained. Our plan is to screen these compounds both on biochemical tests, like tubule assembly, and on cellular tumour models.

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Keywords

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Topic(s)

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Call for proposal

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FP6-2002-MOBILITY-5
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Funding Scheme

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EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

UNIVERSITA DEGLI STUDI DI MILANO
EU contribution
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Total cost

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