A Study of the Binding of Estradiol and 8-Isoestradiol to the Estrogen α-Receptor by Molecular Modeling

The complexes of the estrogen -receptor with estradiol and 8-isoestradiol were comparatively analyzed. The computations of ligand–receptor complexes, carried out using the FLEXX program, allowed us to propose a model for the binding of the analogues of 8-isoestradiol. It was found that rings Cand D of estradiol and 8-isoestradiol are similarly arranged in the ligand-binding pocket and coincide upon the superposition of the corresponding ligand–receptor complexes, whereas rings A and B do not coincide. The oxygen functions in position 17 of the estradiol analogues of both series coincide upon superposition, whereas the phenol 3-hydroxyl groups are 0.05 Å apart. A comparison of the predicted biological properties of modified estradiol analogues of the natural and 8-iso-series with the available experimental data revealed their similarity. Synthetic 2-acetyl analogues of 8-isoestrogens were found to have no uterotropic activity, which is also consistent with the proposed model.     

Synthesis and biological properties of 6-oxa-D-homo-8alpha analogues of steroid estrogens

Modifications of 6-oxa-D-homo-8alpha-analogues of steroid estrogens were found to lead to a complete loss of the uterotropic and hypertriglyceridemic activities. These compounds may be promising for the design on their basis of inhibitors of the steroid hormone metabolism and transporters of other compounds to the estrogen target organs.     

An NMR study of the conformational mobility of 7alpha,8alpha analogues of steroid estrogens

All the signals in the 1H and 13C NMR spectra of some analogues of 7alpha-methyl-8alpha- and 6-oxa-8alpha-steroid estrogens were completely assigned. Considering the values of nuclear Overhauser effect and vicinal coupling constants, these steroids were shown to exhibit a fast, on the NMR time scale, conformational equilibrium arising due to the inversion of ring B. The conformer populations were obtained from a comparison of the experimental and theoretical values of the dihedral angles and the interproton distances. This conformational equilibrium was shown to depend on the nature of atom in position 6: for the 7alpha-methyl-6-oxa-8alpha analogues of the steroid estrogens, the population of the conformer with the pseudoaxial orientation of the 7alpha-methyl group was observed to be decreased compared with the 7alpha-methyl-8alpha analogue.     

An NMR study of the conformational mobility of steroid estrogen 7α-methyl-8α analogues

All the signals in the ¹H and ¹³C NMR spectra of some analogues of 7α-methyl-8α-and 6-oxa-8α-steroid estrogens were completely assigned. Considering the values of nuclear Overhauser effect and vicinal coupling constants, these steroids were shown to exhibit a fast, on the NMR time scale, conformational equilibrium arising due to the inversion of ring B. The conformer populations were obtained from a comparison of the experimental and theoretical values of the dihedral angles and the interproton distances. This conformational equilibrium was shown to depend on the nature of atom in position 6: for the 7α-methyl-6-oxa-8α analogues of the steroid estrogens, the population of the conformer with the pseudoaxial orientation of the 7α-methyl group was observed to be decreased compared with the 7α-methyl-8α analogue.     

Synthesis, structure, and biological properties of some 8alpha-analogues of steroid estrogens with fluorine in position 2

A total synthesis of 8alpha analogues of steroid estrogens with fluorine in position 2 was achieved. Structural features of these compounds were studied by the example of 17beta-acetoxy-2-fluoro-3-methoxy-8alpha-estra-1,3,5(10)-triene. It was shown that the 8alpha analogues of 2-fluorosubstituted steroid estrogens have a low uterotropic activity and retain the osteoprotective and hypocholesterolemic activities.     

Synthesis,structure, and biological properties of some 8α analogues of steroid estrogens with fluorine in position 2

A total synthesis of 8α analogues of steroid estrogens with fluorine in position 2 was achieved. Structural features of these compounds were studied by the example of 17β-acetoxy-2-fluoro-3-methoxy-8α-estra-1,3,5(10)-triene. It was shown that the 8α analogues of 2-fluorosubstituted steroid estrogens have a low uterotropic activity and retain the osteoprotective and hypocholesterolemic activities.     

Effect of TNFα on activities of different promoters of human apolipoprotein A-I gene

Human apolipoprotein A-I (ApoA-I) is a major structural and functional protein component of high-density lipoproteins. The expression of the apolipoprotein A-I gene (apoA-I) in hepatocytes is repressed by pro-inflammatory cytokines such as IL-1β and TNFα. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters in TNFα-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNFα on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNFα leads to activation of the distal alternative apoA-I promoter and downregulation of the proximal alternative and the canonical apoA-I promoters. This effect is mediated by weakening of the promoter competition within human apoA-I 5′-regulatory region (apoA-I promoter switching) in the cells treated by TNFα. The MEK1/2-ERK1/2 cascade and nuclear receptors PPARα and LXRs are important for TNFα-mediated apoA-I promoter switching.