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  • Acknowledgements This work is partially


    Acknowledgements This work is partially supported by the Natural Science Foundation of China(81273353), and the National Science & Technology Key Projects of China (2009ZX09103-085).
    Glyoxalase I (GLO I) is a key enzyme in the pathways leading to glutathione (GSH)-mediated detoxification of methylglyoxal (MG), one of the side products of tumor-specific aerobic glycolysis (Warburg effect). MG is highly reactive with DNA/RNA and proteins, and has been suggested to induce apoptosis in tumor cells. Furthermore, in many human tumors including colon, pancreatic, melanoma, prostate,, breast, and lung, and anticancer drug-resistant human leukemia cells, abnormal expression and higher activity of GLO I have been reported. These observations indicated that the increased expression of GLO I is closely associated with carcinogenesis, , , , , , , and anticancer drug resistance, and that specific inhibitors for GLO I may have therapeutic potential. So, the specific inhibitors of GLO I have been sought as possible effective anticancer drugs, which can selectively kill GLO I-overexpressing and anticancer drug-resistant tumors., Previously, we have identified myricetin, a natural flavonoid Altiratinib that possesses C-4 ketone group and C-5 hydroxy group, as a substrate transition-state mimetic inhibitor of human GLO I. Furthermore, we have recently found delphinidin, the major anthocyanidin present in berry fruits, as a human GLO I inhibitior, which has ability of apoptosis induction in human promyelotic leukemia HL-60 cells. For the aim of designing of novel GLO I inhibitors, we searched new scaffolds from natural compounds using the pharmacophore for GLO I inhibitors derived from myricetin and the library of natural compounds. The workflow of virtual screening (VS) strategy for the discovery of new scaffolds of GLO I inhibitors is as follows (A). The 3D pharmacophore search was performed using Pharmit. Pharmit allows users to specify property filters on the search results, so compounds with molecular weight of more than 300 were Altiratinib filtered out from the search results. The other parameters in Pharmit were used in default settings. The pharmacophore query was defined based on myricetin-based pharmacophore, which derived from structure-activity relationship of human glyoxalase I (GLO I) and flavonoids., Firstly, the GLO I pharmacophore and property filter were applied to the natural compound library (natural db: 120,720 compounds). From this library, 49 compounds fulfilled the criteria (fulfillment of the myricetin pharmacophore (B) and Mw⩽300). Secondly, flavonoid derivatives were removed to select new scaffold compounds (12 compounds). Finally, we selected -stilbene scaffold by virtual inspection (2 compounds). The superimpositions of these two compounds (ZINC14505445 and ZINC35455244) on the myricetin pharmacophore are depicted in C. The stilbene scaffold of these two compounds closely matched the myricetin pharmacophore. Only about 0.002% of compounds have the -stilbene structure fulfilled our criteria in the natural compound library. This screening could achieve scaffold hopping to -stilbene from the GLO I pharmacophore of myricetin. Also, natural -stilbenes commonly found in grape skins and wine have attracted much attention by their potential to prevent human cancers., , Thus, we have chosen the basic structure of -stilbene as the new scaffold of GLO I inhibitors. In order to examine the inhibitory activities to human GLO I of commercially available -stilbenes (A), which possess different positions and numbers of hydroxy and methoxy groups, we performed GLO I assay according to a spectrophotometric method monitoring the increase in absorbance at 240nm due to the formation of --lactoylglutathione as described previously., , As shown in B, among those -stilbene compounds, piceatannol was found to have the most potent inhibitory activity to human GLO I. Noteworthy, 3,3′,4,5′-tetramethoxypiceatannol had little inhibitory activity to GLO I. This result suggests that the four free hydroxy groups of piceatannol strongly contribute to the GLO I inhibitory activity. We next evaluated the dose-dependency of human GLO I inhibitory activity of piceatannol and the IC value was calculated to be 0.76μM (), which is almost the same potency as that of myricetin (IC=0.56μM).