1. Addition of hydrophobic side chains improve the apoptosis inducibility of the human glyoxalase I inhibitor, TLSC702.
- Author
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Azuma M, Inoue M, Nishida A, Akahane H, Kitajima M, Natani S, Chimori R, Yoshimori A, Mano Y, Uchiro H, Tanuma SI, and Takasawa R
- Subjects
- Apoptosis drug effects, Benzene chemistry, Butyrates metabolism, Catalytic Domain, Cell Line, Tumor, Cell Proliferation drug effects, Enzyme Inhibitors metabolism, Glutathione chemistry, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Structure, Protein Binding, Pyruvaldehyde chemistry, Structure-Activity Relationship, Thiazoles metabolism, Butyrates chemistry, Enzyme Inhibitors chemistry, Lactoylglutathione Lyase antagonists & inhibitors, Thiazoles chemistry
- Abstract
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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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