Deuterium Exchange as an Indicator of Hydrogen Bond Donors and Acceptors

Steffel, Lauren R.; Cashman, Timothy J.; Reutershan, Michael H.; Linton, Brian R.

doi:10.1021/ja076185s

Cited by 45 publications

(43 citation statements)

References 20 publications

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“…These observations imply that the compounds do not equilibrate between different conformations on the NMR time-scale, and that in solution each exists predominantly in one form. Temperature coefficient data 56,57 and rates of H/D exchange 58,59 were also measured. Neither set of data were particularly informative, except that they indicate there are no “ endo -cyclic” H -bonds, consistent with the conformations deduced from NMR and calculations that are described immediately below.…”

Section: Resultsmentioning

confidence: 99%

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Xin

Burgess

2016

Org. Biomol. Chem.

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Each amino acid in a peptide contributes three atom units to main-chains, hence natural cyclic peptides can be 9, 12, 15, …. ie 3n membered-rings, where n is the number of amino acids. Cyclic peptides that are 9 or 12-membered ring compounds tend to be hard to prepare because of strain, while their one amino acid homologs (15-membered cyclic pentapeptides) are not conformationally homogeneous unless constrained by strategically placed proline or D-amino acid residues. We hypothesized that replacing one genetically encoded amino acid in a cyclic tetrapeptide with a rigid β-amino acid would render peptidomimetic designs that rest at a useful crossroads between synthetic accessibility and conformational rigidity. Thus this research explored non-proline containing 13-membered ring peptides 1 featuring one anthranilic acid (Anth) residue. Twelve cyclic peptides of this type were prepared, and in doing so the viability of both solution- and solid-phase methods was demonstrated. The library produced contained a complete set of four diastereoisomers of the sequence 1aaf (ie cyclo-AlaAlaPheAnth). Without exception, these four diastereoisomers each adopted one predominant conformation in solution; basically these conformations feature amide N-H vectors puckering above and below the equatorial plane, and approximately oriented their N-H atoms towards the polar axis. Moreover, the shapes of these conformers varied in a logical and predictable way (NOE, temperature coefficient, D/H exchange, circular dichroism). Comparisons were made of the side-chain orientations presented by compounds 1aaa in solution with ideal secondary structures and protein-protein interaction interfaces. Various 1aaa stereoisomers in solution present side-chains in similar orientations to regular and inverse γ-turns, and to the most common β-turns (types I and II). Consistent with this, compounds 1aaa have a tendency to mimic various turns and bends at protein-protein interfaces. Finally, proteolytic- and hydrolytic stabilities of the compounds at different pHs indicate they are robust relative to related linear peptides, and rates of permeability through an artificial membrane indicate their structures are conducive to cell permeability.

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Section: Resultsmentioning

confidence: 99%

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Xin

Burgess

2016

Org. Biomol. Chem.

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“…If the deuterated solvent is used in excess compared to the substrate, then the rate Page 3 of 19 A c c e p t e d M a n u s c r i p t 3 of exchange follows the first order kinetics, which may be called a pseudo first order. The H/D exchange study is utilized to identify the hydrogen bond donors and the acceptors in the molecules using 1 H NMR spectroscopy 43 . Recently the effect of hydrogen bonding on H/D exchange rate in methoxy and keto substituted benzanilides 44 have been reported.…”

Section: Introductionmentioning

confidence: 99%

Study of H/D exchange rates to derive the strength of intramolecular hydrogen bonds in halo substituted organic building blocks: An NMR spectroscopic investigation

Mishra

Suryaprakash

2015

Chemical Physics Letters

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“…This observation supports, in part, the notion of a significant involvement of the NH proton (in the fluorinated analogues) in a fluorine−hydrogen bond. 60 Evidence has been published supporting the concept that a fluorine substituted on an sp 2 carbon can serve as a hydrogen bond acceptor. 61 The presence of a fluorine−hydrogen bond in analogues 8 , 9 , 11 , and 12 is further supported by literature reports confirming the occurrence of hydrogen bonds in 2-fluorobenzamide derivatives.…”

Section: Biological Evaluation and Discussionmentioning

confidence: 99%

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

et al. 2018

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Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (~11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibited proliferation of IGROV1 and A2780 epithelial ovarian cancer cells; in IGROV1 cells with knockdown of FRα, 9, 11, and 12 showed sustained inhibition associated with uptake by PCFT. All compounds inhibited glycinamide ribonucleotide formyltransferase, a key enzyme in the de novo purine biosynthesis pathway. Molecular modeling studies validated in vitro cell-based results. NMR evidence supports the presence of an intramolecular fluorine−hydrogen bond. Potent in vivo efficacy of 11 was established with IGROV1 xenografts in severe compromised immunodeficient mice.

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Deuterium Exchange as an Indicator of Hydrogen Bond Donors and Acceptors

Cited by 45 publications

References 20 publications

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Study of H/D exchange rates to derive the strength of intramolecular hydrogen bonds in halo substituted organic building blocks: An NMR spectroscopic investigation

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

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