Inhibition of cancer derived cell lines proliferation by synthesized hydroxylated stilbenes and new ferrocenyl-stilbene analogs. Comparison with resveratrol

Abstract

Further advances in understanding the mechanism of action of resveratrol and its application require new analogs to identify the structural determinants for the cell proliferation inhibition potency. Therefore, we synthesized new trans-resveratrol derivatives by using the Wittig and Heck methods, thus modifying the hydroxylation and methoxylation patterns of the parent molecule. Moreover, we also synthesized new ferrocenylstilbene analogs by using an original protective group in the Wittig procedure. By performing cell proliferation assays we observed that the resveratrol derivatives show inhibition on the human colorectal tumor SW480 cell line. On the other hand, cell viability/cytotoxicity assays showed a weaker effects on the human hepatoblastoma HepG2 cell line. Importantly, the lack of effect on non-tumor cells (IEC18 intestinal epithelium cells) demonstrates the selectivity of these molecules for cancer cells. Here, we show that the numbers and positions of hydroxy and methoxy groups are crucial for the inhibition efficacy. In addition, the presence of at least one phenolic group is essential for the antitumoral activity. Moreover, in the series of ferrocenylstilbene analogs, the presence of a hidden phenolic function allows for a better solubilization in the cellular environment and significantly increases the antitumoral activity.

Figure 1

(a) Structure of trans-resveratrol (RSV). (b) Structure of cis and trans-resveratrol derivatives.

Figure 2

Molecular structure of synthetic stilbene derivatives. (a) 4-OH stilbenes bearing substituents on cycle B. (b) 4-OH stilbenes bearing substituents on cycle A and/or cycle B. (c) 3-hydroxy-4'-methoxystilbene (10). (d) Stilbenes without free phenolic function.

Figure 3

Molecular structure of ferrocenyl-stilbene analogs 15–17.

Figure 4

Starting reagents for the preparation of ferrocenyl-stilbene analogs 18–20.

Scheme 1

Synthesis of benzylphosphonium bromide 20.

Scheme 2

Synthesis of ferrocenyl-stilbene analogs 15–17.

Figure 5

Effect of stilbene derivatives on human cancerous colorectal SW480 cell viability. Cells were grown for 48 h in the presence of 30 µM resveratrol (or no RSV in a control experiment) or 30 µM stilbene derivatives (numbered on the x-axis). Cell viability was determined by counting cells using the trypan blue test (Co: cells control test). Data correspond to the mean of two independent experiments.

Figure 6

Influence of stilbene derivatives on the cell cycle phases of the SW480 cells line. Cells were grown for 48 h in the presence of 30 µM resveratrol (or no RSV in a control experiment) or 30 µM stilbene derivatives (numbered on the x-axis). After treatment, nuclear DNA was labeled with propidium iodide. The cell cycle effect of the tested compounds was done analysing cell distribution in the different phases of the cell cycle (mean ± standard deviation of two independent experiments).

Figure 7

Effect of stilbenes derivatives on the proliferation of non-transformed IEC18 cells. Cells were grown for 48 h in the presence of 30 µM resveratrol (or no RSV in a control experiment) or 30 µM and 100 µM stilbene derivatives (numbered on the x-axis). Cell viability was determined by counting cells using the trypan blue exclusion. Data correspond to the mean ± standard deviation of two independent experiments.