Structure–activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects

Takasawa, Ryoko; Takahashi, Saki; Saeki, Kazutoshi; Sunaga, Satoshi; Yoshimori, Atsushi; Tanuma, Sei–ichi

doi:10.1016/j.bmc.2008.01.031

Cited by 65 publications

(57 citation statements)

References 16 publications

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“…15) Our previous study has also shown that human GLO I inhibitory flavonoid compounds suppress the growth of HL-60 cells, and their degrees of antiproliferative activity are correlated to the in vitro human GLO I inhibitory activities. 18) Furthermore, delphinidin, the major anthocyanidin present in berry fruits, has been found to have potent inhibitory effect on human GLO I and to induce apoptosis in HL-60 cells in a dose-and time-dependent manner. 23) Taken together, GLO I inhibition is suggested to be an effective contribution to the antiproliferative and proapoptotic activities of TLSC702.…”

Section: Discussionmentioning

confidence: 99%

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TLSC702, a Novel Inhibitor of Human Glyoxalase I, Induces Apoptosis in Tumor Cells

Takasawa

Shimada

Uchiro

et al. 2016

Biological & Pharmaceutical Bulletin

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Human glyoxalase I (hGLO I) is a rate-limiting enzyme in the pathway for detoxification of apoptosisinducible methylglyoxal (MG), which is the side product of tumor-specific aerobic glycolysis. GLO I has been reported to be overexpressed in various types of cancer cells, and has been expected as an attractive target for the development of new anticancer drugs. We previously discovered a novel inhibitor of hGLO I, named TLSC702, by our in silico screening method. Here, we show that TLSC702 inhibits the proliferation of human leukemia HL-60 cells and induces apoptosis in a dose-dependent manner. In addition, TLSC702 more significantly inhibits the proliferation of human lung cancer NCI-H522 cells, which highly express GLO I, than that of GLO I lower-expressing human lung cancer NCI-H460 cells. Furthermore, this antiproliferative effect of TLSC702 on NCI-H522 cells is in a dose-and time-dependent manner. These results suggest that TLSC702 can induce apoptosis in tumor cells by GLO I inhibition, which lead to accumulation of MG. Taken together, TLSC702 could become a unique seed compound for the generation of novel chemotherapeutic drugs targeting GLO I-dependent human tumors. Key words glyoxalase I; inhibitor; anticancer drugGlyoxalase I (GLO I) is a key enzyme in the pathways leading to glutathione (GSH)-mediated detoxification of methylglyoxal (MG), the side product of tumor-specific aerobic glycolysis (Warburg effect). 1) MG is highly reactive with DNA/ RNA and proteins and has been suggested to induce apoptosis in tumor cells.2) Furthermore, in many human tumors including colon, 3) pancreatic, 4) melanoma, 5) prostate, 6,7) breast 8,9) and lung, 10) and anticancer drug-resistant human leukemia cells, 11) abnormal expression and higher activity of GLO I have been reported. These observations indicate that the increased expression of GLO I is closely associated with carcinogenesis [3][4][5][6][7][8][9][10] and anticancer drug resistance. 9) So, specific inhibitors of GLO I have long been sought as possible effective anticancer drugs, which selectively kill GLO I-overexpressing and anticancer drug-resistant tumors. 12,13) Some GSH analogs, such as S-p-bromobenzylglutathione (BBG), 14,15) S-(N-hydroxy-N-methylcarbamoyl) glutathione, 16) and S-(N-aryl-N-hydroxycarbamoyl) glutathione derivatives, 17) have been reported as GLO I inhibitors. However, such GSH analogs are likely to be readily degraded in vivo by ubiquitously distributed γ-glutamyltranspeptidase, a GSH catabolizing enzyme. Probably, they also inhibit other GSH-dependent enzymes. Furthermore, for designing of small molecular GLO I inhibitors, it is not better to use the GSH peptide scaffold as a lead structure because of its flexibility. Therefore, the search of new types of scaffold for GLO I inhibitory small molecules is required to open a way for the development of novel anticancer drugs.Recently, we identified myricetin as a substrate transitionstate mimetic inhibitor of hGLO I.18) Based on the binding mode of myricetin to hGLO I, which was simulated ...

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Section: Discussionmentioning

confidence: 99%

“…18) Based on the binding mode of myricetin to hGLO I, which was simulated by the computational Autodock program, 19) we constructed a hGLO I/inhibitor 4-point pharmacophore. 20) By using the pharmacophore, we discovered TLSC702, which has a unique scaffold and inhibits hGLO I more effectively than BBG 20) (Fig.…”

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confidence: 99%

TLSC702, a Novel Inhibitor of Human Glyoxalase I, Induces Apoptosis in Tumor Cells

Takasawa

Shimada

Uchiro

et al. 2016

Biological & Pharmaceutical Bulletin

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“…The radical scavenging properties of flavonoids are based on the phenol hydroxyl and the possibility of stabilization of the resulting phenoxyl radicals through hydrogen bonding or extended electron delocalization [4]. A number of studies have established the hierarchy of flavonoids in terms of their antioxidant activities and the corresponding structure-activity relationship (SAR) in vitro [5,6]. The existing data are principally focused on the effects of the position and number of hydroxyl group in Abstract Inhibition of free radicals using quercetin, hyperin and rutin is examined to determine their antioxidant effects and the structure-activity relationships of flavonoids.…”

Section: Introductionmentioning

confidence: 99%

Characterization and density functional theory study of the antioxidant activity of quercetin and its sugar-containing analogues

Cai

Chen

Xie

et al. 2013

Eur Food Res Technol

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“…[4][5][6][7][8][9][10][11][12][13][14][15][16] One of the most employed compounds that are derivatives of S-(N-aryl-N-hydroxycarbamoyl) glutathione originally prepared by Creighton and colleagues. [4][5][6][7][8] For example, compounds 1-3 are good inhibitors of human GLO1 (hGLO1), with reported comparable K i value of 46, 10, and 14 nM, respectively (Fig.…”

Section: Design Synthesis and Biological Evaluation Of Potent Human mentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

Tian

Zhai²,

Xiao

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties (10, 10′, 13-15) were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a K i value of 1.0 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (K i =10.0 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors. Its diethyl ester prodrug 10′ was able to penetrate cell membrane and had good inhibitory effect on the growth of NCI-H522 cell xenograft tumor model.

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Structure–activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects

Cited by 65 publications

References 16 publications

TLSC702, a Novel Inhibitor of Human Glyoxalase I, Induces Apoptosis in Tumor Cells

TLSC702, a Novel Inhibitor of Human Glyoxalase I, Induces Apoptosis in Tumor Cells

Characterization and density functional theory study of the antioxidant activity of quercetin and its sugar-containing analogues

Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

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