A. G. Shavva

Catalytic hydrogenation on Raney nickel of estra-1,3,5(10),8,14-pentaenes with sterically accessible double bonds

The catalytic hydrogenation of estra-1,3,5(10),8,14-pentaenes with sterically accessible double bonds in the presence of Raney nickel in 2-propanol at elevated pressure and at heating to 110–120°C resulted in prevailing formation of estrogens 8α-analogs alongside a considerable quantity of estra-5,7,9-trienes. Although the hydrogenation at 45–60°C provided a higher yield of estrogens 8α-analogs, the synthesis of steroids of this group gave better results at hydrogenation in a high purity benzene.

Synthesis and Structure of Some 8α-Analogs of Steroid Estrogens

The distances between the protons of four 8α-analogues of steroid estrogens as determined by X-ray data are consistent with the calculated values obtained by ab initio, PM3 and MM+ methods, that can be used for docking of these stereochemical analogs onto α-estrogen receptors.

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.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.

Molecular structure and biological properties of some 16,16-dimethyl-D-homo-B-nor-9β analogs of steroid estrogens

The interproton distances in the molecule of 17aβ-acetoxy-16,16-dimethyl-3-methoxy-D-homo-Bnor-9β-estra-1,3,5(10)-triene, determined from the X-ray diffraction data and by 1H NMR spectroscopy, were consistent with those calculated ab initio and by the PM3 and MM+ methods. Therefore, MM+ calculations were used to perform docking of a series of D-homo-B-nor-9β-estra-1,3,5(10)-trienes to hormone-binding pocket of estrogen α-receptors, and 16,16-dimethyl-D-homo-B-nor-9-estrone was selected for studying its biological properties. This compound was found to possess cardioprotective activity and no uterotropic effect.

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

Modifications of D-homo-6-oxa-8α-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.

The Synthesis and Properties of B-Nor-8-Isoanalogues of Steroid Estrogens

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.

An NMR Study of the Spatial Structure and Intramolecular Dynamics of Modified Analogues of Steroid Hormones

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.

Ionic hydrogenation of estra-1,3,5(10),8,14-pentaenes

The direction of ionic hydrogenation of estra-1,3,5(10),8,14-pentaenes with triethylsilane in the presence of trifluoroacetic acid is determined by the nature of substituents in the A and B rings. The hydrogenation of 7β-methyl-3-methoxy-D-homo-6-oxaestra-1,3,5(10),8,14-pentaen-17aβ-yl acetate gives mainly 9β-analog, which provides the possibility for synthesizing new inhibitors of enzymes responsible for metabolism of steroidal estrogens.

Synthesis of 6-oxaestra-1,3,5(10),8,14-pentaenes

The Wendler version of the Torgov-Ananchenko scheme of total steroid synthesis was shown to be applicable to the preparation of 6-oxaestra-1,3,5(10),8,14-pentaenes. Conditions for cyclodehydration of secosteroids thus obtained were found, which ensured isolation of the target compounds in a high yield without using chromatographic purification methods.

Synthesis and investigation of the spatial arrangement of the 17β-acetoxy-7α,18-dimethyl-3-methoxy-6-oxaestra-1,3,5(10),8(9)-tetraene

A synthesis was developed of 17β-acetoxy-7α,18-dimethyl-3-methoxy-6-oxaestra-1,3,5(10),8(9)-tetraene. The spatial arrangement of the compound in a crystal and in solution was investigated by means of X-ray diffraction analysis and NMR spectroscopy. The conformation prevailing in solution with the 7α-methyl group in a quasiaxial position corresponds to the structure of the compound in the crystalline state. The presence of a methyl in the 7α position is an important factor governing the osteoprotecting activity of steroids with the similar structure.