Abstract: To simplify the macrocyclic fragment and to modify the zinc binding group of the natural product apicidin, two series of S-hexyl (heptyl) ethanethioate derivatives were designed and synthesized. Twenty-six compounds were synthesized and confirmed with ¹H NMR, IR, MS and HR-MS spectrum, which were not reported. Take vorinostat as control, their antiporliferative activities against cancer cell lines, MCF-7 and HL-60, were tested with MTT assay or trypan blue staining method. Generally in both series it was found that, the chiral carbon atom at 7 position is not necessary, compounds Ⅱ-1, Ⅱ-3, Ⅱ-6 and Ⅱ-13 showed good activity on HL-60 cells in vitro, with the IC₅₀ values less than 10 µmol·L^-1. Ⅱ-7 and Ⅱ-8 showed stronger activity against MCF-7 than Vorinostat, with the IC₅₀ of 3.19 and 6.29 µmol·L^-1, respectively.