Nuclear magnetic resonance studies of amides

Stewart, William E.; Siddall, T. H.

doi:10.1021/cr60267a001

Cited by 1,027 publications

(527 citation statements)

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“…41 The values derived for these two barriers from each of the four pairs of 1 H NMR signals are in excellent agreement (17.1 to 17.8 kcal/mol; Table 3) and are in the range that is often observed for tertiary amides. 35 The E rotamer was found to be more stable than the Z rotamer by about 0.38−0.48 kcal/mol at T c values of 57−104°C.…”

Section: ■ Results and Discussionmentioning

confidence: 94%

“…The two possibilities are that the rotamers are rapidly interconverting on the NMR time-scale or that a single rotamer predominates. 35 Generally, most secondary amides are found to exist as Z rotamers only. 35 The calculated energetics of 1b indicate that the geometry-optimized Z rotamer ( Figure 5) is 5.8 kcal/mol more stable than the E rotamer, which implies that more than 99.99% of 1b exists in Z form in organic solution at room temperature.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Lee

Siméon

Briard

et al. 2012

ACS Chem. Neurosci.

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Eighteen kilodalton translocator protein (TSPO) is an important target for drug discovery and for clinical molecular imaging of brain and peripheral inflammatory processes. PK 11195 [1a; 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinoline carboxamide] is the major prototypical high-affinity ligand for TSPO. Elucidation of the solution structure of 1a is of interest for understanding small-molecule ligand interactions with the lipophilic binding site of TSPO. Dynamic 1 H/ 13 C NMR spectroscopy of 1a revealed four quite stable but interconverting rotamers, due to amide bond and 2-chlorophenyl group rotation. These rotamers have been neglected in previous descriptions of the structure of 1a and of the binding of 1a to TSPO. Here, we used quantum chemistry at the level of B3LYP/ 6-311+G(2d,p) to calculate 13 C and 1 H chemical shifts for the rotamers of 1a and for the very weak TSPO ligand, N-desmethyl-PK 11195 (1b). These data, plus experimental NMR data, were then used to characterize the structures of rotamers of 1a and 1b in organic solution. Energy barriers for both the amide bond and 2′-chlorophenyl group rotation of 1a were determined from dynamic 1 H NMR to be similar (ca.17 to 18 kcal/mol), and they compared well with those calculated at the level of B3LYP/6-31G*. Furthermore, the computed barrier for Z to E rotation is considerably lower in 1a (18.7 kcal/mol) than in 1b (25.4 kcal/mol). NMR (NOE) unequivocally demonstrated that the E rotamer of 1a is the more stable in solution by about 0.4 kcal/mol. These detailed structural findings will aid future TSPO ligand design and support the notion that TSPO prefers to bind ligands as amide E-rotamers.

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Section: ■ Results and Discussionmentioning

confidence: 94%

Section: ■ Results and Discussionmentioning

confidence: 99%

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Lee

Siméon

Briard

et al. 2012

ACS Chem. Neurosci.

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“…Furthermore, the larger covalent [6] and van der Waals [7] radius of sulfur restricts the allowable $,iy angles in the vicinity of thioxo amides [8]. Thioxo peptides are also known to display a higher barrier of rotation about the C-N bond by 8-12 kJ/mol [9]. Amides and thioxo amides differ also in their hydrogen-bond forming properties.…”

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confidence: 99%

Influence on proline‐specific enzymes of a substrate containing the thioxoaminoacyl–prolyl peptide bond

Schutkowski

Neubert

Fischer³

1994

European Journal of Biochemistry

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Dipeptidyl peptidase IV from porcine kidney and aminopeptidase P from Escherichia coli can utilize thioxoalanyl-proline 4-nitroanilide but with decreased kinetic constants compared to the normal substrates. Product analysis showed that exclusively thioxoalanyl-proline was liberated in the case of dipeptidyl peptidase IV catalysis and thioxo-alanine in the case of aminopeptidase-P-mediated thioxo peptide bond hydrolysis. For the proline-specific aminopeptidase P the k,,/K,,, value for the thioxo peptide is 1100-fold lower than for the corresponding 0x0 peptide. This difference is entirely due to k,,,. Because the rotation about the thioxo amide bond is about 12.5 kJ mol-' more difficult than rotation about an amide bond, these data support a mechanism involving rate-limiting rotation about the scissile peptide bond. It was found that the specificity rate constant for the reaction of thioxoalanyl-proline 4-nitroanilide and dipeptidyl peptidase IV is 100 -1000-fold lower compared to the corresponding rate constant for alanyl-proline 4-nitroanilide. This remarkable effect is interpreted in terms of a distorted binding of the transition state for the thioxo substrate. The hydrolysis of the thioxo substrate by dipeptidyl peptidase IV is isomer-specific. The conformation about the nonscissile P,-PI thioxo amide bond has to be in trans for successful cleavage of the scissile peptide bond. We can now directly compare the rotational energy barrier of the prolyl peptide bond for the 0x0 and the thioxo form.Modification of the backbone of biologically active peptides has become increasingly important in the design of analogues possessing greater potency and enzymatic stability. Peptide bond modifications often induce drastic changes in flexibility of the peptide backbone. In contrast X-ray [l], infrared [2], CD [3] and NMR [4J studies of simple thioxo di-and tri-peptides have revealed that a thioxo amide mainly adopts a Z planar configuration similar to an amide, except that the thioxo-carbonyl bond is longer (C=O = 0.124 nm, C=S = 0.164 nm) [l, 51. Furthermore, the larger covalent [6] and van der Waals [7] radius of sulfur restricts the allowable $,iy angles in the vicinity of thioxo amides [8]. Thioxo peptides are also known to display a higher barrier of rotation about the C-N bond by 8-12 kJ/mol [9]. Amides and thioxo amides differ also in their hydrogen-bond forming properties. Thioxo amides are stronger acids [lo] but weaker bases than amides [ll]. Nevertheless, the introduction of a thioxo amide bond is a nearly isosteric substitution for an amide bond [12] often accompanied with surprising effects on the conformaCorrespondence to M. Schutkowski, Max-Planck-Gesellschaft zu Forderung der Wissenschaft e. V.,

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“…The downfield substituent of various N,Ndisubstituted imidates and protonated amides has been assigned (20)(21)(22) as E , just as in amides (23). The only assignment (22) for a protonated primary amide was by analogy of 'JlsNH in amides, and this is opposite to the assignment based on long-range couplings.…”

Section: Signal Assignmentsmentioning

confidence: 99%

Nuclear magnetic resonance studies of proton exchange in imidate esters and amides in strong acid

Perrin¹,

Johnston²

1981

Can. J. Chem.

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. Can. J. Chem. 59,2527Chem. 59, (1981. Saturation-transfer or lineshape measurements of kinetics of proton exchange show that HZ of ethyl acetimidate in 46% H2S04 or ethyl N-methylformimidate in 40% H2S04 exchanges faster than HE, and HE ofprotonated 2-iminotetrahydrofuran exchanges faster than Hz, as expected on the basis of the stabilities of the stereoisomeric imidate esters. In contrast, amide exchange is too fast to measure in aqueous H2S04, but can be measured in 100% H2S04, where HE and HZ exchange at equal rates. Also, there is intramolecular exchange occurring at this same rate. These results are interpreted as evidence for exchange in amides via the N-protonated intermediate, whose lifetime in H2S04 is sufficiently long to permit the protons on nitrogen to become equivalent. By comparing O H exchange with NH exchange, it is concluded that N-protonation is the rate-limiting step. Even though this is a thermodynamically favorable proton transfer in H2S0,, its rate constant is significantly lower than the diffusion-controlled limit. The contrasts between imidate esters and amides and between dilute solutions and H2S04 are discussed. Chem. 59,2527Chem. 59, (1981. L e transfert de saturation ou les mesures de la forme des lignes de la cinetique d'echange du proton montre que le Hz de I'acktimidate d'kthyle dans du H2S04 B 46% ou du N-methylformimidate d'ethyle dans du H2S04 B 40% s'kchange plus rapidement que HE, tandis que le HE de I'imino-2 tetrahydrofuranne protone s'echange plus rapidement que le Hz tel qu'attendu en se basant sur les stabilitks des stCreoisomtres des esters imidates. L'echange d'amide, au contraire, est trop rapide pour &tre mesure dans du H2S04 aqueux mais il peut btre mesure dans du H2S04 a 100%, o i les vitesses d'echange du HE et du Hz sont egales il y a egalement un echange intramoleculaire qui s'effectue B cette mbme vitesse. Les resultats prouvent que l'echange dans les amides se fait via un intermediaire N protone dont le temps de vie dans le H2S04 est suffisamment long pour permettre aux protons sur I'azote de devenir equivalents. En comparant I'Cchange de O H a celui du N H ou conclut que la protonation de I'azote est l'etape determinante. Bien que le transfert de proton dans le H2S04 soit thermodynamiquement favorise, sa constante de vitesse est significativement plus faible que: la limite contr8lte de diffusion. On discute des differences entre les esters imidates et les amides et entre les solutions diluees et de H2S04.[Traduit par le journal] Introduction Two mechanisms have been proposed for acidcatalyzed proton exchange in amides, one involving N-protonation (k, in Scheme 1) (1) and the other a more circuitous one involving the imidic acid (k, and k-,) (2). We originally sought to distinguish between these by comparing rates of exchange of HE and Hz in primary amides (1) (3). We observed that HE exchanges faster, whereas analogy to imidate esters (4) would require HZ to exchange faster if exchange proceeded via the imidic acid. We therefore concluded (3) that exchang...

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Nuclear magnetic resonance studies of amides

Cited by 1,027 publications

References 49 publications

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Influence on proline‐specific enzymes of a substrate containing the thioxoaminoacyl–prolyl peptide bond

Nuclear magnetic resonance studies of proton exchange in imidate esters and amides in strong acid

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Nuclear magnetic resonance studies of amides

Cited by 1,027 publications

References 49 publications

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

Influence on proline‐specific enzymes of a substrate containing the thioxoaminoacyl–prolyl peptide bond

Nuclear magnetic resonance studies of proton exchange in imidate esters and amides in strong acid

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Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry