Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells
Akihiro Ochi, Makoto Yoritate, Tomofumi Miyamoto, Kazuteru Usui, Gorawit Yusakul, Waraporn Putalun, Hiroyuki Tanaka, Go Hirai, Satoshi Morimoto, Seiichi Sakamoto
Abstract
Harringtonine (HT), produced from Cephalotaxus 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′-n-heptyl-4′-demethylharringtonine (1f, n-heptyl derivative) showed the most potent cytotoxicity among the HT ester derivatives produced, with IC50 values of 9.4 nM and 0.4 μM for HL-60 and HeLa cells, respectively. Interestingly, the cytotoxicity of derivative 1f against HL-60 and HeLa cells respectively was ∼5 (IC50 = 50.5 nM) and ∼10 times (IC50 = 4.0 μM) those of HT and ∼2 (IC50 = 21.8 nM) and ∼4 times (IC50 = 1.7 μM) more than homoharringtonine (HHT). These results demonstrate the potential of the derivative 1f as a lead compound against leukemia.