Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells

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 mu M for HL-60 and HeLa cells, respectively. Interestingly, the cytotoxicity of derivative 1f against HL-60 and HeLa cells respectively was similar to 5 (IC50 = 50.5 nM) and similar to 10 times (IC50 = 4.0 mu M) those of HT and similar to 2 (IC50 = 21.8 nM) and similar to 4 times (IC50 = 1.7 mu M) more than homoharringtonine (HHT). These results demonstrate the potential of the derivative 1f as a lead compound against leukemia.

Automated summary

Harringtonine (HT), derived from Cephalotaxus species, displays potent antiproliferative activity against myeloid leukemia cells. By replacing the C-5' methyl group with different hydrocarbon chains, the derivative 1f showed the highest cytotoxicity among the HT ester derivatives produced, exhibiting strong antiproliferative activity against HL-60 and HeLa cells.