Creation of a novel triterpenoid drug that inhibits DNA synthesis 

Abstract

Protoaescigenin, an aglycone of the Olean-12-en, was esterified with tigloyl chloride. Three esterification products: Tig-N, with esterification at C-24 position; Tig-R, with esterification at C-24 and C-28 positions and Tig-S, with esterification at C-24 and C-21 were found to have cell-growth inhibition activity with human ovarian cancer cells (ES2). The IC 50 values for Tig-N, Tig-R and Tig-S are 8.6±5.1µg/ml, 3.6±1.7µg/ml and 0.17±0.20µg/ml, respectively. All compounds have a common C-24 esterification, but Tig-S with the both (C-24 and C-21) esterification has the highest activity. Tig-S induces cell-death by the apoptosis and the drug-treated cells were arrested in the S-phase of cell cycles. Treatment with the esterified products of Protoaescigenin inhibits DNA synthesis in K562 cells in dose and time dependent manner. A drug-combination study of Tig-R with three anticancer drugs: Cytarabine, Camptothecin and Daunomycin, indicated that the drug effect of Tig-R is additive to the drug effect of these agents. This is the first report to show that protoaescigenin esterified with tigloyl groups inhibits DNA synthesis and inhibits cell-growth.