Semisynthetic Esters of 17-Hydroxycativic Acid with in Vitro Cytotoxic Activity against Leukemia Cell Lines.

A collection of sixteen semisynthetic 17-hydroxycativic acid esters with alcohols containing a tertiary amine group was evaluated for their in vitro cytotoxicity against two human cancer cell lines, THP-1 and U937, and for their effects on the cell cycle and cell death. While 17-hydroxycativic acid itself is not cytotoxic, all the esters displayed cytotoxic activity, with 50% growth inhibition (GI) values ranging between 3.2 and 23.1 µM. In general, the most potent compounds in both cell lines were esters with four carbon long alcohol residues. There was no clear relationship between the identity of the terminal secondary amine and the activity of the compound. Experiments using the 6-(pyrrolidin-1-yl)pentyl ester, 2c, revealed that this compound activates caspases-3/7 and causes poly(ADP-ribose)polymerase 1 (PARP-1) fragmentation in THP-1 and U937 cells, indicating the induction of apoptotic cell death. These results suggest that further investigation into the anticancer activity of diterpene derivatives and other labdane diterpenes may be fruitful.