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Communication Dans Un Congrès Année : 2014

Optimization of troglitazone derivatives as potent anti-proliferative agents: towards more active and less toxic compounds

Résumé

Troglitazone (TGZ) belongs to a family of molecules used as anti-diabetic agents. It has been later discovered that such compounds showed interesting anti-proliferative activity. We recently set up a straightforward synthesis of Δ2-TGZ, an unsaturated derivative of TGZ, allowing us to prepare a series of compounds which exhibited much better anti-proliferative activity against hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231) breast cancer cell lines [1]. One drawback of this strategy lies in the hepatotoxicity of TGZ itself, which lead to its withdrawal from the market in 2000 [2].We report here the design and synthesis of new derivatives intended to show a better activity / toxicity profile, via the functionalization of the chromane and thiazolidinedione heterocycles of Δ2-TGZ. Especially, we removed the oxygen atom at the 6-position of the chromane core which was then linked to an alkyl chain via a stable carbon-carbon bond. This was assumed to prevent the formation of the reported hepatotoxic quinone-type metabolites [3]. Furthermore, permuted derivatives of Δ2-TGZ were prepared and evaluated, since such modification based on a ciglitazone template afforded exciting results [4].[1] Salamone, S.; Colin, C.; Grillier-Vuissoz, I.; Kuntz, S.; Mazerbourg, S.; Flament, S.; Martin, H.; Richert, L.; Chapleur, Y.; Boisbrun, M. Eur. J. Med. Chem. 2012, 51, 206-215; [2] Chojkier, M. Hepatology 2005, 41, 237-246; [3] Yokoi, T. Handb. Exp. Pharmacol. 2010, 196, 419-435; [4] Yang, J.; Wei S.; Wang, D.-S.; Wang, Y.-C.; Kulp, S. K.; Chen, C.-S. J. Med. Chem. 2008, 51, 2100-2107.
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Dates et versions

hal-01094539 , version 1 (12-12-2014)

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  • HAL Id : hal-01094539 , version 1

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Andrea Bordessa, Christelle Colin-Cassin, Isabelle Grillier-Vuissoz, Sandra Kuntz, Sabine Mazerbourg, et al.. Optimization of troglitazone derivatives as potent anti-proliferative agents: towards more active and less toxic compounds. 50th International Conference on Medicinal Chemistry, RICT 2014, Jul 2014, Rouen, France. ⟨hal-01094539⟩
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