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Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the ( Z )-2-benzylidene-6-hydroxybenzofuran-3(2 H )-one scaffold that possessed low nanomolar  in vitro  potency in cell proliferation assays using various cancer cell lines,  in vivo  potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were ( Z )-2-((2-((1-ethyl-5-methoxy-1 H -indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile ( 5a ) and ( Z )-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2 H )-one ( 5b ) that inhibited  in vitro  PC-3 prostate cancer cell proliferation with IC 50  values below 100 nM. A xenograft study in nude mice using 10 mg/kg of  5a  had no effect on mice weight, and aurone  5a  did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and  in vitro  inhibition of tubulin polymerization indicated that aurone  5a  disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone  5a  targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones  5a  and  5b  strongly inhibited  in vitro  a panel of human leukemia cancer cell lines and the  in vivo  myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.

scientific reports

Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish