Novel Hydrazine Molecules as Tools To Understand the Flexibility of Vascular Adhesion Protein-1 Ligand-Binding Site: Toward More Selective Inhibitors

Nurminen, Elisa M.; Pihlavisto, Marjo; Lázár, László; Pentikäinen, Ulla; Fülöp, Ferenc; Pentikäinen, Olli T.

doi:10.1021/jm200059p

Cited by 25 publications

(17 citation statements)

References 60 publications

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“…The binding mode is also different from all recent computational studies, where docking and QSAR models of potential VAP-1 inhibitors have been published 19, 20, 30, 37–39 . Unlike 2HP, which binds covalently to TPQ 14 , the molecules 6 , 7 , and 13 bind non-covalently in the channel leading to the active site.…”

Section: Resultsmentioning

confidence: 58%

“…On the contrary, the potency against VAP-1 of another primate, cynomolgus monkey, is very similar to human VAP-1 with compounds 6 , 7 , and 13 . The hydrazine derived inhibitor (1 S ,2 R )-2-(1-methylhydrazino)-1,2-diphenylethanol ( S , S )-tartrate salt (11d) 30 that has been shown to bind irreversibly to the TPQ was used as a control and it inhibits the VAP-1 of both human and rodent species.…”

Section: Resultsmentioning

confidence: 99%

“…Rat total monoamine oxidase enzyme (MAO, mixture of MAO A and MAO B) was prepared from rat liver tissues, homogenized and isolated as described previously 30 . Purified human MAO A and MAO B were purchased from Sigma-Aldrich.…”

Section: Synthesismentioning

confidence: 99%

“…A control compound is equally effective for both species (green). The control compound is (1 S ,2 R )-2-(1-methylhydrazino)-1,2-diphenylethanol ( S , S )-tartrate salt as previously reported 30 .…”

Section: Figurementioning

confidence: 99%

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Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

et al. 2013

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Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor-VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Though they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors.

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Section: Resultsmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

et al. 2013

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“…8 It can be used synthetically to generate an N-N bond as well as a hydrazine linker. There are several reagents that can reduce the N-NO group in order to obtain hydrazine, including Zn/AcOH 9 , LiAH 4 10 , or titanium trichloride (TiCl 3 ) 11 in solution phase, and LiAH 4 8b, 12 or DIBAL 13 on solid-phase. We have found that LiAH 4 or DIBAL do not selectively afford hydrazine efficiently when an amide bond is present, even at low temperatures, such as 0 °C with DIBAL (data not shown), since the amide bond will also be reduced.…”

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confidence: 99%

Parallel Synthesis of 1,6-Disubstituted-1,2,4-triazin-3-ones on Solid-Phase

Huang

Giulianotti

et al. 2013

ACS Comb. Sci.

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A parallel solid-phase synthesis of 1,6-disubstituted-1,2,4-triazin-3-ones from MBHA resin is described. The reduction of resin-bound nitrosamino acids provides hydrazines efficiently without affecting the amide bond. The trityl protected hydrazine is then reduced with borane, and cyclized with 1,1-carbonyldiimidazole. The desired products are cleaved from their solid support and obtained in good yield and purity. This methodology is of value for the rapid parallel preparation of these potentially bioactive molecules.

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Synthesis of N,N‐Disubstituted Hydrazines by Electrocatalytic Addition of Hydrazines to α,β‐Unsaturated Carbonyl Compounds

Xu,

Zhang,

et al. 2024

Adv Synth Catal

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A strategy for the synthesis of N,N‐disubstituted hydrazines via the electrocatalytic addition of hydrazine to α,β‐unsaturated carbonyl compounds is reported. The reaction was carried out under constant current electrolytic conditions in an undivided cell. Using this methodology, various N,N‐disubstituted hydrazines are prepared with 57‐94% yields in 40 min. By adding cyclohexanone and acetic acid to the reaction mixture of N,N‐disubstituted hydrazines and heating for 2 h, a "one‐pot" synthesis of N‐substituted indoles has also been developed. Furthermore, based on cyclic voltammetry and controlled experiments, a plausible mechanism involving the radical pathway is proposed.

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Novel Hydrazine Molecules as Tools To Understand the Flexibility of Vascular Adhesion Protein-1 Ligand-Binding Site: Toward More Selective Inhibitors

Cited by 25 publications

References 60 publications

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Parallel Synthesis of 1,6-Disubstituted-1,2,4-triazin-3-ones on Solid-Phase

Synthesis of N,N‐Disubstituted Hydrazines by Electrocatalytic Addition of Hydrazines to α,β‐Unsaturated Carbonyl Compounds

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