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Accueil > Teams > Pharmacognosy - Chemistry of Natural Products > AMPHICTOT : Total Synthesis of amphidinolides C, C2 et F: Potant marine natural products in the anticancer therapy.

AMPHICTOT : Total Synthesis of amphidinolides C, C2 et F: Potant marine natural products in the anticancer therapy.

AMPHICTOT project was selected from the tender ANR blanc 2011. This project, borne by Bruno Figadère and Laurent Ferrié, will be realized between 2012 and 2015 in the « laboratoire de pharmacognosie» in the université Paris-Sud. The funding, reaching 180k€, allowed notably a recruitment for a PhD position.

The natural products have always been a pool of drug or drug-candidates. In particular in the cancer treatment, important molecules were discovered from nature. The most famous examples in France are taxoids and Vinca alkaloids, isolated from the yew and Madagascar periwinkle respectively (Taxol and Vinorelbine). Besides the research of terrestrial natural product which continues to be a major source of new drug candidates, marine natural products exhibiting some functional diversities and unique structures are at the origin of anticancer drugs (Cytarabine or Yondelis). The fragile and complex ecosystems do not allow farming intensively marine organisms for extraction of metabolites. The only possible route is the total synthesis but the task is tricky because of structural complexity of these natural products, which makes the task arduous. Their syntheses must be inserted in an ambitious research program. The amphidinolides are a group of marine natural product isolated from the dinophlagellate Amphidinum sp. by Kobayashi et al. They characterized more than 30 members in this family from 1986, most of them exhibiting a potent cytotoxicity against human cancer cell lines. The total synthesis of several members of this class has been reported, which of several allowed a reattribution of their stereochemistry. Amphidinolide C is one of the most cytotoxic members of this family, exhibiting in vitro cytotoxicity of 5.8 and 4.6 ng/mL against L1210 murin lymphoma and epidermoid carcinoma KB cells, respectively whereas its congeners, amphidinolides C2 and F, are 1000 times less active and possess very similar structures. Already several works reported synthetic efforts towards the synthesis of amphidinolides C, C2 and F, however no total syntheses have been accomplished until today. We propose to synthesize amphidinolides C, C2 and F by using a convergent three fragment strategies which of one was recently reported by our laboratory. THF moieties of amphidinolides will be synthesized by using methodologies developed in the laboratory. Beyond this primary objective, others secondary objectives will be broached. We must elaborate an efficient strategy to be able to prepare high scale quantities of amphidinolides C, C2 and F in order to evaluate their therapeutic potential. A biological evaluation of advanced intermediates and analogues will be realized. NMR studies will conclude about the original assignment of amphidinolides C, C2 and F and could assess the conformation of the molecules in solution.

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