It has been shown that the derivatives of diethyl 5‐amino‐2‐phthalimidoalkyl‐1,3‐oxazol‐4‐ylphosphonates can be employed in the synthesis of phosphorylated peptidomimetics containing the phosphonoglycine residue. The reaction of diethyl 5‐alkylamino‐2‐aminoalkyl‐1,3‐oxazol‐4‐ylphosphonates with unsaturated azlactones was utilized to obtain phosphorylated peptidomimetics with dehydroamino acid moieties. The double bond in the latter was reduced with zinc in acetic acid to provide the corresponding saturated peptidomimetics containing a diethoxyphosphoryl group in the side chain.

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.

Starting from phthalimidoalkanoylamines 1 we have suggested a synthetic route to 5-amino-1,3-oxazol-4-ylphosphonic acid derivatives 5 , which have been further used to obtain phosphonodipeptides 8, 9, and 10 with the original optical purity retained.

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