Selective cytochrome P450 3A4 inhibitory activity of Amaryllidaceae alkaloids

A library of natural and semi-synthetic Amaryllidaceae alkaloids was screened for cytochrome P450 3A4 (CYP3A4) inhibitory activity. Of the crinane, lycorane and galanthamine representatives examined two semi-synthetic silylated lycorane analogues, accessed via a chemoselective silylation strategy from lycorine, and the natural compound narciclasine exhibited low micromolar activities. Important pharmacological features uncovered include the lack of CYP3A4 inhibitory activity seen for galanthamine and the selective activity that is seen with narciclasine over pancratistatin.

The cytochrome P450 3A4 inhibitory activity of a series of 26 structurally diverse Amaryllidaceae alkaloids and synthetic derivatives is reported. Chemoselective manipulation of the hydroxyl groups in the lycorane series and structure–activity studies provides revealing insight into structural features required for this inhibition.Figure optionsDownload as PowerPoint slide