The inhibition of sustained angiogenesis is an attractive approach for the treatment of cancer, blindness and other angiogenesis-dependent diseases. In this context, our research group has focused on the discovery and characterization of new antiangiogenic compounds isolated from different natural and/or synthetic sources. As an outcome of this search, we previously reported that toluquinol, a methyl hydroquinone isolated from a marine fungus, is an inhibitor of angiogenesis. The fact that the toxicity of several antiangiogenic drugs is one of the main limitations for their clinical use, moved us to synthesise some structural analogues of toluquinol in order to generate drugs with improved antiangiogenic activities and lower toxicities. Our results indicate that (E)-2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol, interferes with different steps of the angiogenic process at lower concentrations than toluquinol, suggesting an improvement in its antiangiogenic potential, what was also confirmed by in vivo assays. A lower toxicity of this new compound is suggested by in vitro, in vivo and in silico studies. The characterization of its mechanisms of action indicates that it inhibits the proliferation of activated endothelial cells, inducing a cell cycle arrest in the G2/M phase. The increased generation of reactive oxygen species, could explain the observed apoptogenic activity of this derivative. A decreased endothelial secretion of MMP-2, an important protease involved in angiogenesis regulation, could play a role in the lower endothelial tubular-like structure formation and migration observed in the presence of this compound. The inhibition of the VEGFR2, Akt and ERK phosphorylation observed when VEGF-activated endothelial cells were treated with (E)-2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol, suggests a possible role of this compound as inhibitor of the VEGF/VEGFR2 axis. Our results indicate that, in contrast with many other low molecular weight inhibitors of angiogenesis, this inhibition is not directly exerted on the tyrosine kinase domain of VEGFR2. Further efforts are warranted in order to establish the potential of this compound as a drug candidate for the treatment of cancer and other angiogenesis-dependent diseases.

(E)-2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol exhibits a lower toxicity and an improved antiangiogenic activity than its natural counterpart, toluquinol

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