Abstract: According to the super-position principle of the reinforcement of biological activities, a series of novel E-substituted 2, 3-diaryl propenoic acyloxy phosphonate derivatives were designed and synthesized. And the structures of the target compounds were confirmed by IR, ¹H NMR, ¹³C NMR and elemental analysis. Furthermore, the cytotoxicities of all compounds on A-549, SGC-7901 and EC-109 in vitro were evaluated by MTT assay, and some of them showed good antitumor activity. Among the active compounds, especially, the IC₅₀ value of compound 3e was (12.7 ± 1.9) μmol·L^-1 against A-549 cells, similar to cisplatin IC₅₀ = (8.0 ± 1.5) μmol·L^-1, compounds 3g and 3k had better inhibition effect on EC-109 cells growth, with the IC₅₀ values of (9.5 ± 1.8) μmol·L^-1 and (11.5 ± 0.9) μmol·L^-1 respectively, and compounds 3i and 3k exhibited good cytotoxic property on A-549, SGC-7901 and EC-109, which were worth further investigation.