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

• Synthesis of new troglitazone derivatives is reported.
• Anti-proliferative activity against breast cancer cell lines showed low micromolar potency.
• Low cytotoxicity towards primary cultured non-malignant human hepatocytes was observed.

Δ2-Troglitazone derivatives were shown to exhibit anti-proliferative activity in a PPARγ-independent manner. We prepared various compounds in order to increase their potency and decrease their toxicity towards non-malignant primary cultured hepatocytes. Many compounds induced viabilities less than 20% at 10 μM on various cancer cell lines. Furthermore, five of them showed hepatocyte viability of 80% or more at 200 μM. In addition, compounds 17 and 18 exhibited promising maximum tolerated doses on a murine model, enabling future investigations.

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