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.
Highlights
Polyphenolic compounds, including stilbenes, anthocyans, catechins and their oligomers, are widespread in a large number of plants
Polyphenolic stilbenoids have been discovered in numerous species, for instance, in the roots of the Asiatic plant Polygonum cuspidatum [1], in the South African plant Erythrophleum lasianthu [2], in red fruit, including grapes [3,4,5], in red wine [6,7], in Itadori green tea [8], in peanuts [9], and in rhubarb [10]
Given the importance of the free phenolic function in position 4 [30,31], we focused on the preparation of derivatives bearing a free phenolic group in position 4 and substituents on the ring B of the stilbenes or on the A and B rings of the stilbenes
Summary
Polyphenolic compounds, including stilbenes, anthocyans, catechins and their oligomers, are widespread in a large number of plants. The modifications of the chemical structure of trans-resveratrol involve the number and the position of the phenolic groups [35,36,37], the presence on the aromatic rings of methoxy groups [38,39,40,41], long alkyl chains [38,42], or functionalized chains [43]. These structural modifications improve mostly the lipophilicity of the stilbenes in the cellular environment and their biological effects inside the cell [44].
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