4-Methylideneisoxazolidin-5-ones—A new class of α-methylidene-γ-lactones with high cytostatic activity

A novel, general method of synthesis of 4-methylideneisoxazolidin-5-ones 10 is described. The target compounds were synthesized starting from ethyl 2-diethoxyphosphoryl-2-alkenoates 6 or dicyclohexylammonium 4-diethoxyphosphoryl-2-alkenoates 7. Addition of N-methylhydroxylamine hydrochloride to these Michael acceptors, lactonization to 4-diethoxyphosphorylisoxazolidin-5-ones 9, and Horner–Wadsworth–Emmons olefination of formaldehyde using 9 gave the title isoxazolidinones 10. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemia cell lines. Several isoxazolidinones 10 were found to be very potent with IC50 < 1 μM. The highest cytostatic activity against HL-60 was observed for 10a and against NALM-6 for 10b with IC50 values of 0.74 and 0.34 μM, respectively.

A series of 4-methylideneisoxazolidin-5-ones was synthesized and their cytostatic activity against L-1210, HL-60, and NALM-6 leukemia cell lines was evaluated. The most potent analogues had IC50 < 1 μM.Figure optionsDownload as PowerPoint slide