Piceatannol, a natural trans-stilbene compound, inhibits human glyoxalase I. Issue 5 (1st March 2017)

• Record Type: Journal Article
• Authors: Takasawa, Ryoko; Akahane, Haruka; Tanaka, Hikari; Shimada, Nami; Yamamoto, Takayuki; Uchida-Maruki, Hiroko; Sai, Masahiko; Yoshimori, Atsushi; Tanuma, Sei-ichi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 5(2017)
• Page Start: 1169
• Page End: 1174
• Publication Date: 2017-03-01
• Subjects: Glyoxalase I -- Inhibitor -- Stilbenes -- Piceatannol -- Anticancer; GLO I Glyoxalase I -- BBGC S-p-bromobenzylglutathione cyclopentyl diester -- GSH glutathione -- HIPC-GSH S-(N-hydroxy-N-indophenylcarbamoyl) glutathione -- NSCLC Non-small cell lung cancer -- PDB Protein Data Bank -- VS virtual screening; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.01.070
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Trans -stilbene scaffold is selected as the new scaffold of GLO I inhibitor. Piceatannol has the potent inhibitory activity against human GLO I. Piceatannol inhibits the proliferation of GLO I-dependent human lung cancer. Two predicted binding modes of piceatannol on human GLO I are proposed. Abstract: Human glyoxalase I (GLO I), a rate-limiting enzyme for detoxification of methylglyoxal (MG), a by-product of glycolysis, is known to be a potential therapeutic target for cancer. Here, we searched new scaffolds from natural compounds for designing novel GLO I inhibitors and found trans -stilbene scaffold. We examined the inhibitory abilities to human GLO I of commercially available trans- stilbene compounds. Among them, piceatannol was found to have the most potent inhibitory activity against human GLO I. Piceatannol could inhibit the proliferation of human lung cancer NCI-H522 cells, which are dependent on GLO I for survival, in a dose- and time-dependent manner. In addition, piceatannol more significantly inhibited the proliferation of NCI-H522 cells than that of NCI-H460 cells, which are less dependent on GLO I. Importantly, overexpression of GLO I in NCI-H522 cells resulted in less sensitive to the antiproliferative activity of piceatannol. Taken together, this is the first report demonstrating that piceatannol inhibits GLO I activity and the GLO I-dependent proliferation of cancer cells. Furthermore, we determined a pharmacophore for novel inhibitors of human GLO I by computational simulation analyses of the binding mode of piceatannol to the enzyme hot spot in the active site. We suggest that piceatannol is a possible lead compound for the development of novel GLO I inhibitory anticancer drugs.