Addition of hydrophobic side chains improve the apoptosis inducibility of the human glyoxalase I inhibitor, TLSC702.
Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure-activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability.
['Azuma|Miku|M|', 'Inoue|Manami|M|', 'Nishida|Aya|A|', 'Akahane|Haruka|H|', 'Kitajima|Masataka|M|', 'Natani|Shunsuke|S|', 'Chimori|Ryusei|R|', 'Yoshimori|Atsushi|A|', 'Mano|Yasunari|Y|', 'Uchiro|Hiromi|H|', 'Tanuma|Sei-Ichi|SI|', 'Takasawa|Ryoko|R|']
D017209:Apoptosis D001554:Benzene D002087:Butyrates D020134:Catalytic Domain D045744:Cell Line, Tumor D049109:Cell Proliferation D004791:Enzyme Inhibitors D005978:Glutathione D006801:Humans D057927:Hydrophobic and Hydrophilic Interactions D007791:Lactoylglutathione Lyase D015394:Molecular Structure D011485:Protein Binding D011765:Pyruvaldehyde D013329:Structure-Activity Relationship D013844:Thiazoles
Apoptosis Glyoxalase I Inhibitor Anticancer Methylglyoxal