Structure-activity studies on the lycorine pharmacophore: A potent inducer of apoptosis in human leukemia cells

Abstract

The direct chemoselective differential functionalization of the ring-C hydroxyl groups present in the Amaryllidaceae alkaloid lycorine is described allowing for selective manipulation of the 1,2-hydroxyl groups. A mini-library comprised of synthetic and natural lycorane alkaloids was prepared and their apoptosis-inducing activity investigated in human leukemia (Jurkat) cells. Further insights into the nature of this interesting apoptosis-inducing pharmacophore are described, including the requirement of both free hydroxyl groups in ring-C.

Graphical abstract

Scheme 1

Structurally diverse alkaloid representatives of the Amaryllidaceae.

Scheme 2

Regio-chemoselective route to 1-acetyllycorine 9.

Fig. 1

Apoptotic index in Jurkat cells after 72 h treatment with compounds 2, 6, 7, 8, 9 and 10. Data for compounds 2 and 6 at 5 μM concentration, and compounds 2, 6 and 9 at 10 μM concentration are statistically significant from control values (p > 0.05).

Fig. 2

Hoechst staining of Jurkat cells treated over 72 h with lycorine and pseudolycorine.

Fig. 3

Hoechst staining of Jurkat cells treated over 72 h with compounds 7, 8 and 9.