New desulfured troglitazone derivatives: Improved synthesis and biological evaluation

Abstract

Breast cancer is a major medical threat which cannot be sufficiently addressed by current therapies because of spontaneous or acquired treatment resistance. Besides, triple-negative breast cancer (TNBC) tumors do not respond to targeted therapies, thus new therapeutic strategies are needed. In this context, we designed and prepared new desulfured troglitazone (TGZ)-derived molecules and evaluated them in vitro for their anti-proliferative activity, with a special focus on triple-negative breast cancer cell lines. Optimization of the synthetic strategies and deracemization of the lead compound were performed to give highly active compound 10 with low-micromolar potency. Further studies revealed that this compound triggers apoptosis rather than cell cycle arrest as observed with TGZ.

Photoisomerization of Arylidene Heterocycles: Toward the Formation of Fused Heterocyclic Quinolines

“…To evaluate the efficiency of the photoinduced isomerization, the stereochemistry of these arylidene heterocycles 1a–w , used as starting materials, was a crucial element and needed a careful investigation. Based on the literature ,− and our own recent works, the stereochemistry was defined as pure ( Z ) for the Ar-TZD derivatives 1a–f , h–m and pure ( E ) for the arylidenepyrrolidine-2,5-diones 1g , n , o . Our hypothesis was confirmed by X-ray diffraction performed on 2- or 3-nitro-benzylidenethiazolidine-2,4-diones 1i or 1j (Figure and Supporting Information section 1) and by 1 H NMR NOESY experiment for 1n and 1w (for details, see Supporting Information section 2).…”

“…In fact, this photoisomerization of BTZD was rarely described in the literature and still remains a synthetic challenge as no systematic study has ever been conducted. In connection with our previous research about the synthesis of BTZD analogues, − we intended to explore this photoisomerization process, starting from a range of substituted BTZDs (Scheme ), to understand how this process can be tuned to select the photoproducts and improve the photoisomerization yields. To reach this objective, we applied a characterization strategy based on UV–vis spectroscopy, and we studied the optical properties, combined with in situ photo-NMR studies, to link these properties to the molecular structures.…”

The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors

“…Compounds TGZ [ 22 ], Δ2-TGZ [ 22 ] and EP 13 [ 23 ] were prepared according to our previously reported procedures. Chemicals and reagents were purchased from Sigma‒Aldrich (Saint-Quentin Fallavier, France), unless otherwise stated.…”

“…In the Δ2 family of compounds, we have shown that deoxygenated and substituted molecules had a higher antiproliferative action and a lower toxicity towards human hepatocytes [ 21 , 22 ]. We recently reported that desulfuration led to a more potent molecule, EP13, which displayed an IC 50 value of 5.8 µM in the estrogen-dependent MCF-7 cells and 5.9 and 8.8 µM in the triple-negative breast cancer cells MDA-MB-231 and Hs578T, respectively, in 2D cultures (compared to 74.3, 45.5 and > 100 µM for TGZ) [ 23 ]. In the present study, our aim was to determine whether EP13 could affect the energy metabolism of breast cancer cells and develop metabolic strategies to eradicate them.…”

Unexplored Vinylic-Substituted 5-Benzylidenethiazolidine-2,4-diones: Synthesis and DFT/NMR Stereochemical Assignment

“…5-Benzylidenethiazolidine-2,4-dione (BTZD) 1 is a privileged scaffold present in a wide range of bioactive molecules including antidiabetics, antivirals, anti-inflammatories, or antiproliferative compounds (Figure ). − …”