Session: Posters:

Angiogenesis, the formation of new blood vessels from other pre-existent ones is transitory and tightly regulated under physiological conditions by a balance of activators and inhibitors. On the contrary, a maintained angiogenesis is related to many pathological conditions, including ophthalmic, cutaneous and inflammatory diseases, as well as cancer, among others. For this reason, angiogenesis inhibition has attracted broad attention in the field of pharmacological research. Encouraged by our previous finding that toluquinol, a methyl hydroquinone isolated from a marine fungus, exhibited an interesting antiangiogenic activity, we have explored the effects of structural modifications of this natural compound in order to develop improved drug candidates. Our results indicate that although the methyl group plays a relevant role in the cytotoxic activity of toluquinol, some derivatives in which this methyl was replaced by another substituent, could keep the antiangiogenic activity, whereas exhibiting a lower cytotoxicity in vitro. Here we describe the activity of a promising toluquinol derivative, (E)-2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol, prepared by mean of a Suzuki coupling reaction, which allowed to replace the methyl group by the vinyl-type substituent. Our data indicate that this compound either keeps or improves the antiangiogenic activity of toluquinol, as demonstrated by a number of in vitro (endothelial cell proliferation, migration and tube formation) and in vivo (chrorioallantoic membrane vascularization and corneal neovascularization in mice) assays. Interestingly, the toxicity of this new compound was lower than that of toluquinol, as demonstrated by means of in vitro studies carried out with transformed and non-transformed cells, and by in vivo studies with zebrafish embryo. Although further studies are needed to elucidate the exact mechanism of action of this toluquinol derivative, our results suggest that it could be related to an induction of apoptosis, as well as to an increase in the levels of reactive oxygen species and a reduction of the reduced glutathione levels, as observed in those endothelial cells that were treated with this compound. The biological activity of this new inhibitor of angiogenesis, along with its lower undesired toxicity suggest an improved potential as drug candidate for angiogenesis-related diseases.

Francisco Sarabia

Appearances