Biotransformation of Hydrazine Dervatives in the Mechanism of Toxicity

Mason, Ronald P.

doi:10.4172/2157-7609.1000168

Cited by 20 publications

(9 citation statements)

References 53 publications

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“…Furthermore, the opening of the 1,3,4-oxadiazole ring can also result from the action of other enzymes as exemplified by HDACs . In either case, hydrazides, the oxadiazole degradation products, can be toxic by themselves or can be further metabolized to genotoxic/mutagenic compounds, such as hydrazines . Taken together, these factors need to be considered when assessing the safety of novel oxadiazole-based HDAC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Motlová,

Šnajdr,

Kutil

et al. 2023

ACS Chem. Biol.

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Histone deacetylase (HDAC) inhibitors used in the clinic typically contain a hydroxamate zinc-binding group (ZBG). However, more recent work has shown that the use of alternative ZBGs, and, in particular, the heterocyclic oxadiazoles, can confer higher isoenzyme selectivity and more favorable ADMET profiles. Herein, we report on the synthesis and biochemical, crystallographic, and computational characterization of a series of oxadiazole-based inhibitors selectively targeting the HDAC6 isoform. Surprisingly, but in line with a very recent finding reported in the literature, a crystal structure of the HDAC6/inhibitor complex revealed that hydrolysis of the oxadiazole ring transforms the parent oxadiazole into an acylhydrazide through a sequence of two hydrolytic steps. An identical cleavage pattern was also observed both in vitro using the purified HDAC6 enzyme as well as in cellular systems. By employing advanced quantum and molecular mechanics (QM/MM) and QM calculations, we elucidated the mechanistic details of the two hydrolytic steps to obtain a comprehensive mechanistic view of the double hydrolysis of the oxadiazole ring. This was achieved by fully characterizing the reaction coordinate, including identification of the structures of all intermediates and transition states, together with calculations of their respective activation (free) energies. In addition, we ruled out several (intuitively) competing pathways. The computed data (ΔG ‡ ≈ 21 kcal·mol–1 for the rate-determining step of the overall dual hydrolysis) are in very good agreement with the experimentally determined rate constants, which a posteriori supports the proposed reaction mechanism. We also clearly (and quantitatively) explain the role of the −CF3 or −CHF2 substituent on the oxadiazole ring, which is a prerequisite for hydrolysis to occur. Overall, our data provide compelling evidence that the oxadiazole warheads can be efficiently transformed within the active sites of target metallohydrolases to afford reaction products possessing distinct selectivity and inhibition profiles.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Motlová,

Šnajdr,

Kutil

et al. 2023

ACS Chem. Biol.

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“…In the case of hydralazine, the primary amine is oxidized [28] followed by transfer of the radical site to the aromatic ring and loss of the diamino group. Then, either the resulting intermediate loses another electron, forming a stable phtalazine, or might react with the heme group leading to irreversible modification and inhibition of MPO ( Figure 12A).…”

Section: Discussionmentioning

confidence: 99%

“…The one-electron oxidation of hydralazine by horseradish peroxidase (HRP) is known to produce hydralazyl radicals which then decompose to form various products or react with molecular oxygen to generate reactive oxygen-centered radicals [28]. Figure S4C).…”

Section: Oxidation Products Of Hydralazine and Zinc1mentioning

confidence: 99%

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

et al. 2017

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The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic inflammatory diseases. Because of the deleterious effects of circulating MPO released from phagocytosing neutrophils, there is a great interest in the development of new efficient and specific inhibitors. It has been demonstrated that the interaction between the inhibitor and the active site is not the only key factor playing a role in the inhibition. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening combined to drug-likeness filters. Starting from a set of 727,842 compounds, 30 molecules were selected by this virtual method and tested for inhibition of the chlorination activity of MPO. Twelve out of 30 compounds were found to have an IC50 less than 5 µM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (Zinc1) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (Zinc3) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that Zinc1 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration. Pharmacomodulation has been performed to optimize the activity of Zinc1.

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“…9 Hydrazine traps these active molecules and inhibits necessary life activities, i.e. , nucleic acid and lipid metabolism, 10,11 amino acid decarboxylation and transamination, 12,13 and mitochondrial oxidation. 14 Moreover, the generation of free radical intermediates, 15 e.g.…”

Section: Introductionmentioning

confidence: 99%

Near-infrared fluorescent turn-on probe for hydrazine detection: environmental samples and live cell imaging

et al. 2023

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Biotransformation of Hydrazine Dervatives in the Mechanism of Toxicity

Cited by 20 publications

References 53 publications

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6)

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

Near-infrared fluorescent turn-on probe for hydrazine detection: environmental samples and live cell imaging

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