Conformational studies of novel estrogen receptor ligands by 1D and 2D NMR spectroscopy and computational methods

Sebag, Albert B.; Hanson, Robert N.; Forsyth, David; Lee, Choon Young

doi:10.1002/mrc.1150

Cited by 15 publications

(9 citation statements)

References 14 publications

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“…All of the 1 H assignments in Table 1 are within 0.1 ppm of literature assignments by Kumar and Schneider 21 and Bischofberger et al 22 The 13 C assignments are also consistent (within an average deviation of 0.8 ppm) with literature values obtained for similar molecules and carbon environments using computational approaches 18,23 and 2D NMR, 24 and for E2 17 in acetone-d 6 (within an average deviation of 1.12 ppm). The 1 H and 13 C NMR assignments are the first reported for E2 in DMSO-d 6 .…”

Section: Discussionsupporting

confidence: 84%

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Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR

et al. 2005

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The NMR-derived structure of estrogen (17b-estradiol, E2), the drug of choice for postmenopausal women, was compared with a recent literature crystal x-ray structure of Fab-bound E2.1 H and 13 C NMR spectra of E2 were acquired in DMSO-d 6 . Assignments were obtained from an analysis of DQF-COSY, TOCSY, HETCOR, HMQC and HMBC 2D NMR spectra. The 1 H and 13 C NMR assignments are the first reported for E2 in DMSO-d 6 . Two solution structures, S1 and S2, were obtained with molecular modeling using NOE constraints. S1 overlaps with the crystal structure for all rings. S2 shows prominent differences in the C-ring (C9-C11-C12-C13) segment, which deviates from a chair conformation, and excellent overlap in the A-, B-and D-rings of E2. The C-ring in S2 adopts a boat conformation as opposed to a chair conformation in the x-ray and S1 structures. The S2 structure is about 6• more twisted than the bound x-ray and S1 models. The S1, S2 and x-ray structures had ring bowing values of 10.1 ± 0.3, 11 ± 1 and 10.37• , respectively. Of the 100 solution conformers generated, 83 had S1 conformation and 17 had S2 conformation, with average internal energies of 112 ± 2 and 141 ± 2 kcal mol −1 , respectively. The 100 S1-and S2-derived conformers showed a r.m.s.d. of 0.72Å for all atoms. The x-ray, S1 and S2 C18 -O17 distances were 2.93, 2.92 ± 0.01 and 2.93 ± 0.01Å, respectively, and the O3 -O17 distances were 11.06, 11.18 ± 0.12, and 10.89 ± 0.05Å, respectively.

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Section: Discussionsupporting

confidence: 84%

“…As noted in Sebag et al, 18 selective irradiation of the methyl (Me) H18 group should lead to enhancement of only protons on theˇ-face of the C-and D-rings. Looking at the structures for S1 and S2, Me-H18 (0.63 ppm) is on the same side of the rings as H8 (1.27 ppm) with the shortest distance between them being 2.2Å.…”

Section: Nmrmentioning

confidence: 77%

Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR

et al. 2005

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“…Our analyses revealed that H15α and H15β assignments were interchanged earlier (37). The stereochemical assignments made here on five-membered rings are further supported by recent studies on similar molecules, 17β-estradiol, 17β-hydroxyandrosta-1,4-dien-3-one, (17α,20E)-(p-trifluoromethylphenyl)vinylestradiol, and (17α,20E)-(o-trifluoromethylphenyl)vinylestradiol (42)(43)(44).…”

Section: Discussionsupporting

confidence: 83%

¹H and ¹³C NMR characterization and stereochemical assignments of bile acids in aqueous media

Ijare

Somashekar

Jadegoud

et al. 2005

Lipids

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The unconjugated bile acids cholic acid, deoxycholic acid, and chenodeoxycholic acid; their glycine and taurine conjugates glycocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid; and a taurine conjugated ursodeoxycholic acid, tauroursodeoxycholic acid, were characterized through 1H and 13C NMR in aqueous media under the physiological pH region (7.4 +/- 0.1). Assignments of 1H and 13C signals of all the bile acids were made using a combination of several one- and two-dimensional, homonuclear (1H-1H) and heteronuclear (1H-13C) correlations as well as spectral editing NMR methods. Stereochemical assignment of the five-membered ring of the bile acids is reported here for the first time. The complete characterization of various bile acids in aqueous media presented here may have implications in the study of the pathophysiology of biliary diseases through human biliary fluids using NMR spectroscopy.

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Moreover, its quality is also good enough to determine finer structural differences such as isomeric, conformational or tautomeric structures. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Moreover, its quality is also good enough to determine finer structural differences such as isomeric, conformational or tautomeric structures.…”

Section: Introductionmentioning

confidence: 99%

Quantum chemical calculations of³¹P NMR chemical shifts: scopes and limitations

Latypov

Polyancev

Yakhvarov

et al. 2015

Phys. Chem. Chem. Phys.

122

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The aim of this work is to convince practitioners of (31)P NMR methods to regard simple GIAO quantum chemical calculations as a safe tool in structural analysis of organophosphorus compounds. A comparative analysis of calculated GIAO versus experimental (31)P NMR chemical shifts (CSs) for a wide range of phosphorus containing model compounds was carried out. A variety of combinations (at the HF, DFT (B3LYP and PBE1PBE), and MP2 levels using 6-31G(d), 6-31+G(d), 6-31G(2d), 6-31G(d,p), 6-31+G(d,p), 6-311G(d), 6-311G(2d,2p), 6-311++G(d,p), 6-311++G(2d,2p), and 6-311++G(3df,3pd) basis sets) were tested. On the whole, it is shown that, in contrast to what is claimed in the literature, high level of theory is not needed to obtain rather accurate predictions of (31)P CSs by the GIAO method. The PBE1PBE/6-31G(d)//PBE1PBE/6-31G(d) level can be recommended for express estimation of (31)P CSs. The PBE1PBE/6-31G(2d)//PBE1PBE/6-31G(d) combination can be recommended for routine applications. The PBE1PBE/6-311G(2d,2p)//PBE1PBE/6-31+G(d) level can be proposed to obtain better results at a reasonable cost. Scaling by linear regression parameters significantly improves results. The results obtained using these combinations were demonstrated in (31)P CS calculations for a variety of medium (large) size organic compounds of practical interest. Care has to be taken for compounds that may be involved in exchange between different structural forms (self-associates, associates with solvent, tautomers, and conformers). For phosphorus located near the atoms of third period elements ((CH3)3PS and P(SCH3)3) the impact of relativistic effects may be notable.

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Conformational studies of novel estrogen receptor ligands by 1D and 2D NMR spectroscopy and computational methods

Cited by 15 publications

References 14 publications

Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR

Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR

¹H and ¹³C NMR characterization and stereochemical assignments of bile acids in aqueous media

Quantum chemical calculations of³¹P NMR chemical shifts: scopes and limitations

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Conformational studies of novel estrogen receptor ligands by 1D and 2D NMR spectroscopy and computational methods

Cited by 15 publications

References 14 publications

Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR

Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR

1H and 13C NMR characterization and stereochemical assignments of bile acids in aqueous media

Quantum chemical calculations of31P NMR chemical shifts: scopes and limitations

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Product

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¹H and ¹³C NMR characterization and stereochemical assignments of bile acids in aqueous media

Quantum chemical calculations of³¹P NMR chemical shifts: scopes and limitations