SN2 reactions at amide nitrogen – theoretical models for reactions of mutagenic N-acyloxy-N-alkoxyamides with bionucleophiles

Glover, Stephen A.

doi:10.3998/ark.5550190.0002.c15

Cited by 6 publications

(7 citation statements)

References 9 publications

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“…[1][2][3][4][5] In this case, the amides are electrophilic agents, reacting with nucleophiles at the nitrogen with displacement of the acyloxyl group. 4,[6][7][8][9][10][11][12] Since they were first synthesised, they have been shown to be direct-acting mutagens and a wide number that have been tested in the Ames reverse mutation assay are mutagenic towards Salmonella typhimurium TA100 without the requirement for metabolic activation. 4,7,[13][14][15][16][17][18][19][20][21][22] Well over a hundred congeners have now been synthesised and tested and several quantitative structure activity relationships (QSAR's) have evolved that can explain, with reasonable accuracy, their mutagenic activity in TA100.…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator

et al. 2016

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N-Acyloxy-N-alkoxyamides are direct-acting mutagens in S. typhimurium TA100 with a linear dependence upon log P that maximises at log P0 = 6.4. Eight N-acyloxy-N-alkoxyamides (2-9) bearing a naphthalene group on any of the three side-chains and with log P0 < 6.4 have been demonstrated to be significantly and uniformly more mutagenic towards S. typhimurium TA100 than 50 mutagens without naphthalene. The activity enhancement of 2-9 is likely due to intercalative binding of naphthalene to bacterial DNA as a number are also active in TA98, a frame-shift strain of S. typhimurium, which is modified by intercalators. DNA damage profiles for naphthalene-bearing mutagens confirm enhanced reactivity with DNA when naphthalene is incorporated and a different binding mode when compared to mutagens without naphthalene. The effect is independent of whether the naphthalene is attached to an electron-donating alkyl or electron-withdrawing acyl group, alkyl tether length or, in the case of 6 and 7, the point of attachment to naphthalene. A new quantitative structure activity relationship has been constructed for all 58 congeners incorporating log P and an indicator variable, I, for the presence (I = 1) or absence (I = 0) of naphthalene and from which the activity enhancing effect of a naphthalene has been quantified at between three and four log P units. Contrary to conventional views, simple naphthalene groups could target molecules to DNA through intercalation.

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Section: Introductionmentioning

confidence: 99%

Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator

et al. 2016

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“…Reactions of 21 systems with amines and thiols have been modelled at the AM1, HF/6-31G(d), and pBP/DN* levels, which reveal significant charge separation in the transition states and alkoxynitrenium ion character (Figure 12) [86]. These reactions should be favoured by electron-donor substituents on the nucleophile and electron-acceptor substituents on the acyloxyl group.…”

Section: Reactivity Of Anomeric Amidesmentioning

confidence: 99%

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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“…In addition, by analogy with bis-heteroatom-substituted carbon, such amides usually exhibit ground-state anomeric effects through the amide nitrogen, which influence their conformation and reactivity. With a good leaving group at nitrogen ( 1a and 1b ), n Y –σ* NX overlap weakens the N–X bond and they can undergo both S N 1 and S N 2 reactions at the amide nitrogen. − With weaker leaving groups ( 1d or with 1b in nonpolar solvents), the anomeric effect drives the unusual HERON reaction in which anomeric destabilization results in migration of a substituent, X, from nitrogen to the carbonyl carbon with attendant formation of a Y-atom-stabilized nitrene (Scheme ). ,− …”

Section: Introductionmentioning

confidence: 99%

Structures of N,N-Dialkoxyamides: Pyramidal Anomeric Amides with Low Amidicity

et al. 2011

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The first X-ray structures of two anomeric N,N-dialkoxyamides (2 and 3) have been obtained, which confirm that they are highly pyramidalized at nitrogen and have long N-CO bonds, a characteristic of other anomeric amides and a consequence of drastically reduced amidicity. The crystals also demonstrate chirality at the amide nitrogen in the solid state. The structures are well-predicted by density functional calculations using N,N-dimethoxyacetamide as a model. The amidicity of N,N-dimethoxyacetamide has been estimated by two independent methods, COSNAR and a new transamidation method, which give almost identical resonance stabilization energies of -8.6 kcal mol(-1) and only 47% that of N,N-dimethylacetamide computed at the same level. The total destabilization is composed of a resonance and an inductive contribution, which we have evaluated separately. The electronegative oxygens at nitrogen are responsible for localization of the nitrogen lone pair on the amide nitrogen, a factor that contributes to a loss of resonance over and above the impact of pyramidalization at nitrogen, as well as the fact that N,N-dimethoxyacetamide is predicted to protonate on the carbonyl oxygen in preference to nitrogen.

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SN2 reactions at amide nitrogen – theoretical models for reactions of mutagenic N-acyloxy-N-alkoxyamides with bionucleophiles

Cited by 6 publications

References 9 publications

Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator

Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator

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

Structures of N,N-Dialkoxyamides: Pyramidal Anomeric Amides with Low Amidicity

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