Abstract：
:Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, specific inhibitors of this enzyme have been expected as effective anticancer drugs. The purpose of this study is a good construction of the human GLO I/inhibitor pharmacophore to obtain unique human GLO I inhibitory seed compounds for the development of useful anticancer drugs. Here, we selected natural flavonoid compounds that possess a plane configuration of cis C-4 ketone and C-5 hydroxy groups as the substrate (MG) transition-state mimetic structure. These compounds were examined the inhibitory abilities to human GLO I activity and analyzed their structure-activity relationships to determine an important pharmacophore of flavonoids for the human GLO I binding. Our results point to the contribution of hydroxy groups at the B ring of flavonoids to the effective inhibition of the human GLO I. Based on the binding mode of flavonoids, we constructed the human GLO I/inhibitor pharmacophore. This work delivers the first three-dimensional (3D) structural data and explains certain flavonoids interact specifically with the human GLO I.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Takasawa R,Takahashi S,Saeki K,Sunaga S,Yoshimori A,Tanuma Sdoi
10.1016/j.bmc.2008.01.031subject
Has Abstractpub_date
2008-04-01 00:00:00pages
3969-75issue
7eissn
0968-0896issn
1464-3391pii
S0968-0896(08)00048-5journal_volume
16pub_type
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