FerroPodo : Synthesis of Ferrocenyl-Podophyllo Analogs and their Evaluation as Anti-Tumor Agents

(Synthèse d'analogues ferrocényl à la podophylotoxine)

Axe Application - Chimie de la santé

Projet de recherche mené du 01/10/12 au 30/09/13

Laboratoires porteurs
Liste de mots clés 

Podophyllotoxin, ferrocenyl, a antiproliferative tests, multi-step synthesis, Mizoroki-Heck reaction


Podophyllotoxin is a natural product endowed of a high antimitotic activity and a high affinity for tubulin. Its action results in the cessation of cell division, inducing cell death. However, its high toxicity restrains its use as drug. To overcome this drawback, several chemical modifications of the native podophyllotoxin have been made. However, to date, no reports have so far been directed toward incorporation of a metallocene moiety.

The search for new organometallic drugs is a central field in drug discovery, including the domain of cancer therapy. In particular, metallocenyl moieties are known to increase the selectivity of drugs toward cancer cells, the conjugate organometallic compound reducing the damage of healthy tissues, yet permitting the desired antimitotic and cytotoxic effects of the active principle.

In this study, we report the synthesis of two new podophyllotoxin analogs incorporating a ferrocenyl moiety and the preliminary antiproliferative tests of these conjugates on two breast cancer lines. While the former compound has been straightforwardly obtained by esterification between podophyllotoxin and ferrocenecarboxylic acid, the latter molecule, incorporating rings A, B and C of podophyllotoxin and carrying the ferrocenyl appendage in place of ring E of podophyllotoxin, required a 6-step synthesis starting from 6-bromopiperonal and ferrocene. Key steps in the synthesis were a challenging benzhydrylation generating a quaternary center, and an intramolecular Mizoroki-Heck reaction, which formed ring C of the target molecule. Such original structures have been discussed in terms of the importance of ferrocenyl conjugated motifs to generate antiproliferative effects.

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