Harringtonine (HT), produced from species, is known to exhibit potent antiproliferative activity against myeloid leukemia cells by inhibiting protein synthesis. A previous study using acute promyelocytic leukemia (HL-60) cells raised the possibility that the C-5' methyl group of HT plays an important role in regulating leukemia cell line antiproliferative activity. In order to investigate the effect of hydrocarbon chains at C-5' on the resultant activity, the C-5' methyl group was replaced with various straight- and branched-chain hydrocarbons using the corresponding alcohols, and their antiproliferative activity against HL-60 and HeLa cells was investigated. As a result, 4'--heptyl-4'-demethylharringtonine (, -heptyl derivative) showed the most potent cytotoxicity among the HT ester derivatives produced, with IC values of 9.4 nM and 0.4 μM for HL-60 and HeLa cells, respectively. Interestingly, the cytotoxicity of derivative against HL-60 and HeLa cells respectively was ∼5 (IC = 50.5 nM) and ∼10 times (IC = 4.0 μM) those of HT and ∼2 (IC = 21.8 nM) and ∼4 times (IC = 1.7 μM) more than homoharringtonine (HHT). These results demonstrate the potential of the derivative as a lead compound against leukemia.
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