The role of steric effects in the direct mutagenicity of N-acyloxy-N-alkoxyamides

Andrews, Luke E.; Bonin, Antonio M.; Fransson, Linda E.; Gillson, Ashley-Mae E.; Glover, Stephen A.

doi:10.1016/j.mrgentox.2006.02.003

Cited by 18 publications

(27 citation statements)

References 22 publications

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“…Readily synthesised by treatment of N -alkoxy- N -chloroamides 2a , themselves a form of anomeric amide, with silver or sodium carboxylate salts in anhydrous solvents [45,46,48,49], NAA’s are direct-acting mutagens which react with nucleophilic centres in DNA [31,39,40,41,42,43,44,45,46,49,50]. Additionally, they react with a variety of nucleophiles to produce other congeners, including, reactive anomeric amides in the form of N -alkoxy- N -aminoamides 2d [44,47,51] and N -alkoxy- N -thioalkylamides 2e [52].…”

Section: Properties Of Anomeric Amidesmentioning

confidence: 99%

“…The amide carbonyl facilitates S N 2 reactivity in line with enhanced reactivity in phenacyl bromides [89]. In particular, bimolecular reaction rates are radically impeded with branching α to the carbonyl [50], which is analogous to the resistance to S N 2 reactions of α-halo ketones bearing substituents at the α’ position [90,91]. …”

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

“…Mutagenicity towards S. typhimurium in the Ames reverse mutation assay does not require premetabolic activation [92,93]. Our DNA damage studies on plasmid DNA at physiological pH, as well as extensive structure–activity relationships [31,38,39,40,41,43,45,46,48,49,50,79,80], point to binding of NAA’s 21 , intact, into the major groove of DNA, where an S N 2 reaction occurs at the most nucleophilic centre, the electron-rich N7 in guanine (Scheme 1 vii) [94,95,96,97]. All three side chains (R 1 , R 2 , and R 3 ) of 21 have an impact upon both DNA damage profiles as well as mutagenicity levels.…”

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

“…An S N 1 mechanism, yielding electrophilic N -acyl- N -alkoxynitrenium ions, was ruled out since only R 1 and R 2 would influence binding and reactivity. Moreover, mutagenic activity is radically reduced when there is branching α to the carbonyl in parallel with the impaired S N 2 reactivity [40,50,51]. The mutagenic activity of N -acyloxy- N -alkoxyamides 21 has been used recently to show how hydrophobicity and intercalating side chains impact upon DNA binding [38,39].…”

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

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Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

Glover

Rosser

2018

Molecules

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This review describes how resonance in amides is greatly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, evaluated computationally, can be reduced to as little as 50% that of N,N-dimethylacetamide. However, this occurs without significant twisting about the amide bond, which is borne out both experimentally and theoretically. In certain configurations, reduced resonance and pronounced anomeric effects between heteroatom substituents are instrumental in driving the HERON (Heteroatom Rearrangement On Nitrogen) reaction, in which the more electronegative atom migrates from nitrogen to the carbonyl carbon in concert with heterolysis of the amide bond, to generate acyl derivatives and heteroatom-substituted nitrenes. In other cases the anomeric effect facilitates SN1 and SN2 reactivity at the amide nitrogen.

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Section: Properties Of Anomeric Amidesmentioning

confidence: 99%

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

See 2 more Smart Citations

Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

Glover

Rosser

2018

Molecules

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“…ecology, human health, risk assessment. There are a number of studies dedicated to mutagenicity models using quantitative structure–activity relationships (QSAR) (2–4).…”

mentioning

confidence: 99%

Simplified Molecular Input Line Entry System‐Based Optimal Descriptors: Quantitative Structure–Activity Relationship Modeling Mutagenicity of Nitrated Polycyclic Aromatic Hydrocarbons

2009

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We developed a new QSAR model, based on the optimal descriptors, calculated with simplified molecular input line entry system. These descriptors are correlated with mutagenic potential for a training set and correlated with this end-point for a test set. Statistical characteristics of the model are n = 28, r 2 = 0.902, q 2 = 0.892, s = 0.554, F = 240 (training set) and n = 20, r 2 = 0.853, q 2 = 0.823, s = 0.702, F = 105 (test set).

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N ‐(Benzyloxy)‐ N ‐(pivaloyloxy)‐4‐(trifluoromethyl)‐benzamide

Berger,

Dherange,

Morales

et al. 2024

Organic Syntheses

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This chapter presents the procedure for the N‐(Benzyloxy)‐N‐(pivaloyloxy)‐4‐(trifluoromethyl)‐benzamide which belongs to the N‐(alkoxy)‐N‐(acyloxy)benzamide class of anomeric amides. In this class of compounds, in order to satisfy the electron demand of the two oxygen substituents, the resonance of the nitrogen lone pair with the amide carbonyl is largely diminished. This results in an sp 3 configuration and pyramidalization at nitrogen. The authors have used N‐(Benzyloxy)‐N‐(pivaloyloxy)‐4‐(trifluoromethyl)‐benzamide to selectively edit secondary amines containing a range of functional groups and heterocycles. Nitrogen deletion of cyclic secondary amines results in a ring contraction, which has been applied to give substituted cyclobutene products from pyrrolidine precursors. This methodology also enabled a new synthetic route to the chemotherapeutic Pemetrexed and enabled the late‐stage editing of the kinase inhibitor Lapatinib.

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The role of steric effects in the direct mutagenicity of N-acyloxy-N-alkoxyamides

Cited by 18 publications

References 22 publications

Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

Simplified Molecular Input Line Entry System‐Based Optimal Descriptors: Quantitative Structure–Activity Relationship Modeling Mutagenicity of Nitrated Polycyclic Aromatic Hydrocarbons

N ‐(Benzyloxy)‐ N ‐(pivaloyloxy)‐4‐(trifluoromethyl)‐benzamide

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