Taxol derivatives are selective inhibitors of DNA polymerase α

Abstract

During screening for mammalian DNA polymerase inhibitors, we found and succeeded in isolating a potent inhibitor from a higher plant, Taxus cuspidate. The compound was unexpectedly determined to be taxinine, an intermediate of paclitaxel (taxol) metabolism. Taxinine was found to selectively inhibit DNA polymerase α (pol.α) and β (pol.β). We therefore, tested taxol and other derivatives and found that taxol itself had no such inhibitory effect, and only taxinine could inhibit both pol.α and β. The other compounds used, one derivative, cephalomannine, and five intermediates synthesized chemically inhibited only the pol.α activity in vitro. None of the compounds, including taxinine, influenced the activities of the other DNA polymerases, which are reportedly targeted by many pol.β inhibitors. With both pol.α and β, all of the compounds tested noncompetitively inhibited with respect to both the DNA template-primer and the dNTP substrate.