7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines

Ohwada, Tomohiko; Ishikawa, Satoko; Mine, Yusuke; Inami, Keiko; Yanagimoto, Takahiro; Karaki, Fumika; Kabasawa, Yoji; Otani, Yuko; Mochizuki, Masahito

doi:10.1016/j.bmc.2011.02.049

Cited by 16 publications

(15 citation statements)

References 41 publications

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“…11,14,15 Our compounds are expected to be useful biological tools for further studies on agonist-induced desensitization of β 2 -AR. Furthermore, there is considerable theoretical and experimental evidence that nitrogen-pyramidalized N-nitroso 7-azabicyclo[2.2.1]heptane derivatives (such as WNNOs) are not mutagenic, 24 and if this is confirmed, our compounds might also be potential candidates for clinical application.…”

Section: Discussionmentioning

confidence: 94%

“…In this study, we aimed to generate watersoluble N-nitrosamines (WNNOs) of 7-azabicyclo[2.2.1] heptanes, which resemble conformationally constrained N-nitrosoproline derivatives ( Figure 1). 23,24 We found that the resulting compounds were soluble and stable in water, and they exhibit nitrosylation reactivity to thiols, which could be used as functional mimics of GSNO in terms of S-nitrosylation but not in terms of direct generation of NO. We also examined the ability of these WNNOs to block desensitization of β 2 -AR signaling on agonist (ISO) stimulation.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 94%

mentioning

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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“…An aromatic electron-withdrawing substituent (p-CF 3 in 12) retarded the NO release relative to the unsubstituted case (10). The distal aromatic ring of 6 had no significant effect on the NO release as compared with the methyl ester 5.…”

Section: Nitrosamine L Max [Nm]mentioning

confidence: 87%

“…In any case, the present bicyclic nitrosA C H T U N G T R E N N U N G amines have been reported to be nonmutagenic in the typical Ames assay, apparently due to their characteristic strained structures. [10] Results and Discussion Spectroscopic features of bicyclic and monocyclic nitros-A C H T U N G T R E N N U N G amines: We have previously shown that the amino-nitrogen atom of nitrosamine derivatives of 7-azabicyclo-A C H T U N G T R E N N U N G [2.2.1]heptanes is pyramidal and the N À NO bond tends to be weak. [9] Electronic absorption spectra of various synthesized nitrosamines (Scheme 1) were measured in DMSO (e.g., 3 and 16, Figure 1 and Table 1).…”

Section: Introductionmentioning

confidence: 99%

Visible‐Light‐Triggered Release of Nitric Oxide from N‐Pyramidal Nitrosamines

Karaki

Kabasawa

Yanagimoto

et al. 2011

Chemistry A European J

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Although many organic/inorganic compounds that release nitric oxide (NO) upon photoirradiation (phototriggered caged-NOs) have been reported, their photoabsorption wavelengths mostly lie in the UV region, because X-NO bonds (X=heteroatom and metal) generally have rather strong π-bond character. Thus, it is intrinsically difficult to generate organic compounds that release NO under visible light irradiation. Herein, the structures and properties of N-pyramidal nitrosamine derivatives of 7-azabicyclo[2.2.1]heptanes that release NO under visible light irradiation are described. Bathochromic shifts of the absorptions of these nitrosamines, attributed to HOMO (n)-LUMO (π*) transitions associated with the nonplanar structure of the N-NO moiety, enable the molecules to absorb visible light, which results in N-NO bond cleavage. Thus, these compounds are innate organic caged-NOs that are uncaged by visible light.

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“…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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7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines

Cited by 16 publications

References 41 publications

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

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

Visible‐Light‐Triggered Release of Nitric Oxide from N‐Pyramidal Nitrosamines

Transnitrosylation Directs TRPA1 Selectivity in N-Nitrosamine Activators

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