Synthesis of 2,3-di- and 2,2,3-trisubstituted-3-methoxycarbonyl-γ-butyrolactones as potent antitumor agents

• Multicomponent synthesis of densely substituted paraconic acid analogs.
• In vitro cytotoxicity evaluation of the compounds in human cancer cell lines.
• Sub-micromolar activity of one of the tested compounds.
• Determination of the mode of action using flow cytometry.
• Activation of the apoptotic cascade without prominent blockade of the cell cycle.

Various 2,3-substituted γ-butyrolactones have been synthesized by three-component reaction of aryl bromides, dimethyl itaconate and carbonyl compounds. The in vitro cytotoxic activity of these products was evaluated against a representative panel of cancer cell lines (KB, HCT116, MCF7, MCF7R, PC3, SK-OV3, HL60 and HL60R). One compound (4x) displays a good anti-proliferative activity with IC50 in the sub-micromolar range. The mechanism of action has been investigated using flow cytometry.

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