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

Abstract

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.

The conformations of 17β-estradiol (E2) and 17α-estradiol as determined by solution NMR

“…The C-18 methyl group gave NOEs with H 8 , H 11β , H 12β , H 15β and H 16β for both 17β-estradiol (E2) and 17α-estradiol, and NOE of the C-18 methyl with H 17 for 17α-estradiol was also observed (Figure 4). We did not, however, observe the reported16 NOE between H 12β and H 15β for E2 which was due to their mis-assignment of the proton resonances. Interestingly, the NOESY of H 1 with H 11α in the plane of the aromatic ring gave a negative NOE, an unusal effect 20,21.…”

“…Estrogen receptors are activated by the hormone 17β-estradiol (E2) but not by the 17α-estradiol isomer (Figure 1). 14,15 Recently, the structure of the estrogen hormone 17β-estradiol (E2) as determined by NMR and X-ray was reviewed 16. In addition to the low energy C-ring chair conformation that corresponded well to crystal structures, a second conformation with a twisted boat C-ring was proposed for E2 in dimethylsulfoxide solution 16…”

Synthesis and Molecular Structure of D-Homo-B-nor-8α Analogs of Steroidal Estrogens

“…These data indicate that further experimental studies on such estrogen analogs may be promising. Modified steroidal estrogens possessing the above properties are almost unknown [2]; therefore, information on molecular structure of D-homo-B-nor-8α analogs of steroidal estrogens may be useful in the design of new compounds with changed spectrum of biological activity.In the first step, structural parameters of model compounds in crystal and in solution are usually compared with those calculated by nonempirical and semiempirical methods [3][4][5][6]. As model steroids we selected 16,16-dimethyl-D-homo-B-nor-8α-estrone methyl ether (I) for which X-ray diffraction data are available [1] and 1-methoxy-4-methyl-D-homo-B-nor-8α-estra-1,3,5(10)-trien-17a-one (II), taking into account that representatives of this stereochemical series with substituents on C 1 and C 4 were not reported.…”

“…In the first step, structural parameters of model compounds in crystal and in solution are usually compared with those calculated by nonempirical and semiempirical methods [3][4][5][6]. As model steroids we selected 16,16-dimethyl-D-homo-B-nor-8α-estrone methyl ether (I) for which X-ray diffraction data are available [1] and 1-methoxy-4-methyl-D-homo-B-nor-8α-estra-1,3,5(10)-trien-17a-one (II), taking into account that representatives of this stereochemical series with substituents on C 1 and C 4 were not reported.…”

Molecular structures of some D-homo-6-oxa-8α analogs of steroidal estrogens

“…Since a number of computer programs can be used to model the bonding of proteins with ligands [17][18][19][20], it is expedient to use one or another method for calculating the conformation of the ligand with respect both to its docking in the hormone that bonds a section of the protein and to comparison of the conformations of the ligand in the solution and in the complex with the proteins. The first stage of the investigations involves comparison of the conformations of the ligands obtained experimentally and calculated by the various methods [21][22][23][24].…”