Structural Features of Aliphatic <i>N</i>-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes That Facilitate N−NO Bond Cleavage

Ohwada, Tomohiko; Miura, M.; Tanaka, Haruko; Sakamoto, Shigeru; Yamaguchi, Kentaro; Ikeda, Hirotaka; Inagaki, Satoshi

doi:10.1021/ja010917d

Cited by 85 publications

(76 citation statements)

References 32 publications

(30 reference statements)

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“…6 Also the 1,3-acyl shi path I for R 0 ¼ alkyl and O(t-Bu) leads to radical pair generation following nitrogen extrusion from the diazo compound C. 7 Although the N-N homolysis path III is the more unusual transformation, it can occur either through photolysis 2 or thermally as demonstrated by Koenig 5 for R ¼ cyclopropyl and R 0 ¼ t-butoxy, it is a potential source of biologically useful NO donors. 8 All of the chemistry in Scheme 1 pertains to the secondary nitrosamides, in which R ¼ aryl, alkyl, or alkoxy groups.…”

Section: Introductionmentioning

confidence: 99%

Lewis acid stabilization and activation of primary N-nitrosamides

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Lewis acid stabilization and activation of primary N-nitrosamides

et al. 2017

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“…the Griess assay (Ohwada et al, 2001;Yanagimoto et al, 2007). An aromatic group (NNO-ABBH1-NNO-ABBH4) and electron-withdrawing groups, such as trifluoromethyl (NNO-ABBH1) and ester (NNO-ABBH2 and NNO-ABBH3) groups, enhanced N-NO bond cleavage (NNO-ABBH1 .…”

Section: Trpa1 Subtype Selectivity Of Nitrosaminesmentioning

confidence: 99%

“…S-Nitrosoglutathione is a biological transnitrosylating agent, but also releases NO (Foster et al, 2003;Makita et al, 2013). N-Nitroso derivatives of ABBH (7-azabenzobicyclo[2.2.1]heptanes) constitute a new class of NO donors that, at physiological pH and temperature, transnitrosylate thiols to generate S-nitrosothiols without releasing NO (Ohwada et al, 2001(Ohwada et al, , 2011Yanagimoto et al, 2007;Karaki et al, 2012). This article describes the development of ABBH N-nitrosamines into subtype-selective nitrosylation activators of TRP channels.…”

Section: Introductionmentioning

confidence: 99%

Transnitrosylation Directs TRPA1 Selectivity in N-Nitrosamine Activators

et al. 2013

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S-Nitrosylation, the addition of a nitrosyl group to cysteine thiols, regulates various protein functions to mediate nitric oxide (NO) bioactivity. Recent studies have demonstrated that selectivity in protein S-nitrosylation signaling pathways is conferred through transnitrosylation, a transfer of the NO group, between proteins via interaction. We previously demonstrated that sensitivity to activation by synthetic NO-releasing agents via S-nitrosylation is a common feature of members of the transient receptor potential (TRP) family of Ca 21 -permeable cation channels. However, strategies to confer subtype selectivity to nitrosylating agents targeted to TRP channels are yet to be developed. Here, we show selective activation of TRPA1 channels by novel NO donors derived from the ABBH (7-azabenzobicyclo[2.2.1]heptane) N-nitrosamines, which exhibit transnitrosylation reactivity to thiols without releasing NO. The NNO-ABBH1 (N-nitroso-2-exo,3-exo-ditrifluoromethyl-7-azabenzobicyclo[2.2.1]heptane) elicits S-nitrosylation of TRPA1 proteins, and dose-dependently induces robust Ca 21 influx via both recombinant and native TRPA1 channels, but not via other NO-activated TRP channels. TRPA1 activation by NNO-ABBH1 is suppressed by specific cysteine mutations but not by NO scavenging, suggesting that cysteine transnitrosylation underlies the activation of TRPA1 by NNO-ABBH1. This is supported by the correlation of N-NO bond reactivity and TRPA1-activating potency in a congeneric series of ABBH N-nitrosamines. Interestingly, nonelectrophilic derivatives of ABBH also activate TRPA1 selectively, but less potently, compared with NNO-ABBH1. Thus, ABBH N-nitrosamines confer subtype selectivity on S-nitrosylation in TRP channels through synergetic effects of two chemical processes: cysteine transnitrosylation and molecular recognition of the nonelectrophilic moiety.

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“…We synthesized a series of ethylene glycolcontaining molecules (WNNOs; Figure 1), which exhibited different strengths of the N-NO bond, as estimated by Griess assay (diazo-coupling-based dye formation assay under acidic conditions) in 100% H 2 O (Figure 1). 30 The evaluation of water solubility of WNNO6 and WNNO6a-b (see Online Table I) indicated that the triethylene glycol unit affords adequate water solubility. The single carboxylic acid functionality of compound WNNO5 (Figure 1) did not significantly improve the aqueous solubility (2 mmol/L; Online Table I).…”

Section: Successful Synthesis Of Water-soluble and Stable Compounds Imentioning

confidence: 99%

Attenuated Desensitization of β-Adrenergic Receptor by Water-Soluble N-Nitrosamines That Induce S-Nitrosylation Without NO Release

Makita

Kabasawa

Otani

et al. 2013

Circulation Research

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Rationale: The clinical problem of loss of β-adrenergic receptor (β-AR) response, both in the pathogenesis of heart failure and during therapeutic application of β-agonists, is attributable, at least in part, to desensitization, internalization, and downregulation of the receptors. In the regulation of β-AR signaling, G protein–coupled receptor kinase 2 (GRK2) primarily phosphorylates agonist-occupied β-ARs, and this modification promotes desensitization, internalization, and downregulation of β-ARs. It has been demonstrated that GRK2 is inhibited by its S-nitrosylation. However, compounds that induce S-nitrosylation, such as S-nitrosoglutathione, simultaneously generate NO, which has been demonstrated to operate for cardiovascular protection. Objective: We examine whether S-nitrosylation without NO generation inhibits desensitization of β 2 -AR by GRK2. We thus aim to synthesize compounds that specifically induce S-nitrosylation. Methods and Results: We have developed water-soluble N-nitrosamines that have S-nitrosylating activity but lack NO-generating activity. These compounds, at least partly, rescue β-AR from desensitization in HEK 293 cells expressing FLAG-tagged human β 2 -AR and in rat cardiac myocytes. They inhibit isoproterenol-dependent phosphorylation and internalization of β 2 -AR. Indeed, they nitrosylate GRK2 in vitro and in cells, and their S-nitrosylation of GRK2 likely underlies their inhibition of β 2 -AR desensitization. Conclusions: Compounds that induce S-nitrosylation without NO release inhibit GRK2 and attenuate β 2 -AR desensitization. Developing water-soluble drugs that specifically induce S-nitrosylation may be a promising therapeutic strategy for heart failure.

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Structural Features of Aliphatic N-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes That Facilitate N−NO Bond Cleavage

Cited by 85 publications

References 32 publications

Lewis acid stabilization and activation of primary N-nitrosamides

Lewis acid stabilization and activation of primary N-nitrosamides

Transnitrosylation Directs TRPA1 Selectivity in N-Nitrosamine Activators

Attenuated Desensitization of β-Adrenergic Receptor by Water-Soluble N-Nitrosamines That Induce S-Nitrosylation Without NO Release

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