3,5-Disubstituted-thiazolidine-2,4-dione analogs as anticancer agents: Design, synthesis and biological characterization

A series of 2,5-disubstituted-thiazolidine-2,4-dione analogs based on the newly identified lead 1, a potential anticancer agent via the inhibition of the Raf/MEK/extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades, were synthesized and biologically characterized. A new lead structure, 15, was identified to have improved anti-proliferative activities in U937 cells, to induce apoptosis in U937, M12 and DU145 cancer cells, and to arrest U937 cells at the S-phase. Furthermore, Western blot analysis demonstrated a correlation of the anti-proliferative activity and blockade of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Collectively, these results strongly encourage further optimization of 15 as a new lead with multi-target properties to develop more potent compounds as anticancer agents.

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► Thiazolidine-2,4-dione analogs have anticancer activity.
► We designed and synthesized a series of 3,5-disubstituted-thiazolidine-2,4-dione analogs as anticancer candidates.
► Synthesized compounds were tested in various human cancer cell lines.
► Compound 15 was identified as a new lead compound to develop more potent analogs.