Caffeic acid phenethyl ester derivatives inhibit glyoxalase I activity and induce cell death in cultured cancer cell lines.

Glyoxalase I (GLO I) is the rate-limiting enzyme responsible for the detoxification of methylglyoxal, a toxic byproduct of anaerobic glycolysis. GLO I is highly expressed in various tumors and has therefore been recognized as a promising target for cancer therapy. We previously identified several cis-diol-containing polyphenols, namely, myricetin, delphinidin, and piceatannol, as potent inhibitors of human GLO I, inducing cell death in GLO I-dependent cancer cells. In this study, we examined the inhibitory abilities to GLO I of another cis-diol-containing polyphenol, caffeic acid phenethyl ester (CAPE). CAPE showed potent GLO I inhibitory activity with an IC50 value of 7.9 ± 1.2 μM and antiproliferative effects on GLO I-dependent cancer cell lines. In contrast, caffeic acid and phenethyl alcohol, the components of CAPE, did not show GLO I inhibitory activity and exerted drastically lower effects on cancer cell proliferation than CAPE. Caffeic acid benzyl ester and phenyl ester possessed similar inhibitory effects as CAPE, whereas methyl ester showed a notably weaker effect than CAPE. We selected nine compounds (CAD-01-CAD-09) in silico using caffeic acid n-butyl ester as a query molecule. Among these compounds, CAD-09 exhibited a sixfold increase in GLO I inhibition than CAPE and showed a statistically significant antiproliferative effect on HL-60 cells. Overall, caffeic acid esters may provide a promising structural framework for the development of GLO I inhibitors with anticancer potential.