Glyoxalase I inhibitor

S-(N-Aryl-N-hydroxycarbamoyl)glutathione derivatives have been proposed as possible anticancer agents, because of their ability to strongly inhibit the methylglyoxal-detoxifying enzyme glyoxalase I. Glyoxalase I inhibitor is a potent inhibitor of glyoxalase I.

In vitro: As a tumor-selective anticancer agent, Glyoxalase I inhibitor [3(Et)2] was evaluated against B16 melanotic melanoma, L1210 murine leukemia, and nonproliferating murine splenic lymphocytes in culture. The diethyl ester prodrugs of Glyoxalase I inhibitor [3(Et)2] also displayed significant tumour-selective toxicity towards L1210 cells compared with normal murine splenic lymphocytes in vitro [1].

In vivo: Small-scale efficacy studies indicated that 3b(Et)2 could effectively inhibit tumour growth in plasma esterase-deficient mice bearing murine B16 melanoma and in esterasedeficient athymic nude mice bearing androgen-independent human prostate PC-3 tumours or human colon HT-29 tumours [2].

Clinical trial: No clinical data are available.

References:
[1] Kavarana MJ, Kovaleva EG, Creighton DJ, Wollman MB, Eiseman JL.  Mechanism-based competitive inhibitors of glyoxalase I: intracellular delivery, in vitro antitumor activities, and stabilities in human serum and mouse serum. J Med Chem. 1999;42(2):221-8.
[2] Creighton DJ, Zheng ZB, Holewinski R, Hamilton DS, Eiseman JL.  Glyoxalase I inhibitors in cancer chemotherapy. Biochem Soc Trans. 2003;31(Pt 6):1378-82.

TLSC702, a Novel Inhibitor of Human Glyoxalase I, Induces Apoptosis in Tumor Cells.[Pubmed:27150153]

Biol Pharm Bull. 2016;39(5):869-73.

Human glyoxalase I (hGLO I) is a rate-limiting enzyme in the pathway for detoxification of apoptosis-inducible 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.

Synthesis of azide derivative and discovery of glyoxalase pathway inhibitor against pathogenic bacteria.[Pubmed:24076169]

Bioorg Med Chem Lett. 2013 Nov 15;23(22):6138-40.

A glyoxalase inhibitor was synthesized and tested against Staphylococcus aureus for first time and showed MIC90 of 20 mug/ml. Henceforth, we synthesized unnatural azide derivative of the same inhibitor to improve the biological activity. In that order, an azide carboxylate was synthesized from dimethyl tartrate by tosylation and azide substitution. The synthesized, azide compound was coupled with glutathione derivative in high yield and tested against S. aureus and showed improved MIC90 of 5 mug/ml. In general, it can be also easily converted to unnatural beta-amino acid in good yield. The shown methodology will be extended to study induced suicide in Burkholderia mallei, Francisella tularensis and Mycobacterium tuberculosis in future.

Structural basis for 18-beta-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor.[Pubmed:26279158]

Acta Pharmacol Sin. 2015 Sep;36(9):1145-50.

AIM: Glyoxalase I (GLOI), a glutathione (GSH)-dependent enzyme, is overexpressed in tumor cells and related to multi-drug resistance in chemotherapy, making GLOI inhibitors as potential anti-tumor agents. But the most studied GSH analogs exhibit poor pharmacokinetic properties. The aim of this study was to discover novel non-GSH analog GLOI inhibitors and analyze their binding mechanisms. METHODS: Mouse GLOI (mGLOI) was expressed in BL21 (DE3) pLysS after induction with isopropyl-beta-D-1-thiogalactopyranoside and purified using AKTA FPLC system. An in vitro mGLOI enzyme assay was used to screen a small pool of compounds containing carboxyl groups. Crystal structure of the mGLOI-inhibitor complex was determined at 2.3 A resolution. Molecular docking study was performed using Discovery Studio 2.5 software package. RESULTS: A natural compound 18-beta-glycyrrhetinic acid (GA) and its derivative carbenoxolone were identified as potent competitive non-GSH analog mGLOI inhibitors with Ki values of 0.29 mumol/L and 0.93 mumol/L, respectively. Four pentacyclic triterpenes (ursolic acid, oleanolic acid, betulic acid and tripterine) showed weak activities (mGLOI inhibition ratio <25% at 10 mumol/L) and other three (maslinic acid, corosolic acid and madecassic acid) were inactive. The crystal structure of the mGLOI-GA complex showed that the carboxyl group of GA mimicked the gamma-glutamyl residue of GSH by hydrogen bonding to the glutamyl sites (residues Arg38B, Asn104B and Arg123A) in the GSH binding site of mGLOI. The extensive van der Waals interactions between GA and the surrounding residues also contributed greatly to the binding of GA and mGLOI. CONCLUSION: This work demonstrates a carboxyl group to be an important functional feature of non-GSH analog GLOI inhibitors.