In search of a cytostatic agent derived from the alkaloid lycorine: synthesis and growth inhibitory properties of lycorine derivatives

Abstract

As a continuation of our studies aimed at the development of a new cytostatic agent derived from an Amaryllidaceae alkaloid lycorine, we synthesized 32 analogues of this natural product. This set of synthetic analogues included compounds incorporating selective derivatization of the C1 versus C2 hydroxyl groups, aromatized ring C, lactamized N6 nitrogen, dihydroxylated C3-C3a olefin functionality, transposed olefin from C3-C3a to C2-C3 or C3a-C4, and C1 long-chain fatty esters. All synthesized compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines including those exhibiting resistance to proapoptotic stimuli and representing solid cancers associated with dismal prognoses, such as melanoma, glioblastoma, and non-small-cell lung cancer. Most active analogues were not discriminatory between cancer cells displaying resistance or sensitivity to apoptosis, indicating that these compounds are thus able to overcome the intrinsic resistance of cancer cells to pro-apoptotic stimuli. 1,2-Di-O-allyllycorine was identified as a lycorine analogue, which is 100 times more potent against a U373 human glioblastoma model than the parent natural product. Furthermore, a number of synthetic analogues were identified as promising for the forthcoming in vivo studies.

Figure 1

Lycorine derivatives obtained through selective protection of the C2-hydroxyl [% yields are from lycorine (1)]

Figure 2

Illustration of the in vitro growth inhibitory effects of lycorine and 17 of its derivatives in four cancer cell lines that are sensitive to proapoptotic stimuli (the hatched bars) versus four cancer cell lines that display resistance to pro-apoptotic stimuli (the black bars). The data are presented as mean ± SEM values. We included in the present analysis all the compounds displaying GI₅₀ values < 100 μM in each of the eight cancer cell lines under study (see Table).

Scheme 1

Synthesis of known and new derivatives of lycorine starting with diacetate 2

Scheme 2

Synthesis of a new polyhydroxylated analogue 13

Scheme 3

Selective functionalization of the C1 and C2-hydroxyl functionality

Scheme 4

Preparation of C1- and C2-benzoates

Scheme 5

Synthesis of aromatic derivatives

Scheme 6

Synthesis of dicarbonate and diether derivatives and C3a-quaternization/olefin transposition using Claisen rearrangement