Synthesis and cytotoxic activity evaluation of a small library of resveratrol-related stilbenoids

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids present a wide structural diversity and mediate a great number of biological responses relevant for human health. In particular, resveratrol is known to modulate several pathways directly linked to cancer progression, as well as its analogue pterostilbene, characterized by increased metabolic stability and significant pharmacological activities. In order to study the potential cytotoxicity of other natural stilbenoids, a small collection of simplified analogues has been synthesized and tested on melanoma A375, non-small cell lung cancer H460 and prostate PC3 tumour cell lines and human normal skin WS1 fibroblasts. The structural determinants responsible for the activity have been highlighted, indicating that both lipophilicity and geometry of the most potent molecules might play a role on their antiproliferative activity. Moreover, to evaluate the ability of the selected molecules to produce DNA damage, the expression of the γ-H2AX after compound exposure was evaluated in WS1, H460 and A375 cell lines. Low levels of DNA damage were evidenced in normal WS1 fibroblasts exposed to 200 µM resveratrol, whereas in H460 and A375 lines the compound showed a significant damaging activity, confirming its selective behaviour towards cancer cells. In the same way, stilbenoid analogues showing a conjugated benzofuran moiety revealed a very interesting profile compared to other already known derivatives. Further studies are still ongoing in order to identify more precise structure-activity relationships on resveratrol congeners.