ABSTRACT
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.
Subject(s)
Estrenes/chemical synthesis , Estrogens/chemical synthesis , Fluorine , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Bone Density/drug effects , Bone Density Conservation Agents/chemical synthesis , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacology , Cholesterol/blood , Estrenes/chemistry , Estrenes/pharmacology , Estrogens/chemistry , Estrogens/pharmacology , Female , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
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.
Subject(s)
Estrogens/chemistry , Steroids/chemistry , Magnetic Resonance Spectroscopy , Molecular Conformation , SolutionsABSTRACT
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.
Subject(s)
Estrogens/chemical synthesis , Steroids/chemical synthesis , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Bone and Bones/anatomy & histology , Bone and Bones/drug effects , Cholesterol/blood , Estrogens/chemistry , Estrogens/pharmacology , Female , Organ Size/drug effects , Ovariectomy , Rats , Rats, Sprague-Dawley , Receptors, Progesterone/biosynthesis , Stereoisomerism , Steroids/chemistry , Steroids/pharmacology , Structure-Activity Relationship , Sulfatases/antagonists & inhibitors , Triglycerides/blood , Uterus/anatomy & histology , Uterus/drug effects , Uterus/metabolismABSTRACT
The study of the binding of estradiol B-nor-8-isonalogues to estrogen receptors from the rat uterus helped create the proposed model of the corresponding ligand-receptor complexes. The use of this model ensured the choice of such micromodifications in this steroid group that sharply decreased their hormonal activity. By the example of 16,16-dimethyl-D-homo-B-nor-8-isoestrone, we demonstrated the possibility of the synthesis of the estrogen analogues devoid of uterotropic activity but retaining immunosuppressive activity.
Subject(s)
Estrogens/chemical synthesis , Estrone/analogs & derivatives , Estrone/chemical synthesis , Animals , Crystallography, X-Ray , Estradiol/analogs & derivatives , Estradiol/chemistry , Estradiol/pharmacology , Estrogens/chemistry , Estrogens/pharmacology , Estrone/chemistry , Estrone/pharmacology , Female , Immunoglobulin E/biosynthesis , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Ligands , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Models, Molecular , Molecular Structure , Organ Size , Ovariectomy , Rats , Rats, Wistar , Receptors, Estrogen/chemistry , Uterus/drug effectsABSTRACT
Special features of the use of homo- and heteronuclear correlation methods of NMR in one and two dimensions for studying the spatial structure and intramolecular dynamics of modified analogues of steroid hormones (MASH) are considered. The application of these methods to the assignment of resonances in the high-field 1H NMR region and to the determination of the most stereospecifically important parameters, such as the vicinal constants of spin-spin coupling (3JH-H) and nuclear Overhauser effects (NOE), are discussed using the example of NMR studies of some estrogens and androgens at 300 MHz and on the basis of literature data. The most efficient combination of the methods and the necessary modification of each of them may be chosen considering the spectral and relaxation parameters of MASH in liquid medium, including the anisotropy of the overall diffusive motion. The characteristics of MASH are the wide use of correlations through long-range couplings (COSY-45 and DQF-COSY), the application of the 4,5JH-H constants for the determination of spatial structure, and the advantage of heteronuclear HSQC methods with and without 13C decoupling over the corresponding HMQC methods in both resolution and sensitivity. In the conformationally rigid MASH molecules, the anisotropy of the MASH diffusive motion in liquid adversely affects the determination of interproton distances by the calibrating processing method for the NOE difference and NOESY spectra: it results in both overestimated and underestimated distance values depending on the polar angle ratios of the reference and the determined distances. Under certain conditions, conformationally mobile MASH demonstrate the additional contribution of the scalar relaxation mechanism between the indirectly (scalarly) bound protons. This mechanism is responsible for the underestimated values of NOE and the corresponding errors in the distance determination.
