New analogs of steroid estrogens

Abstract

Aiming at the investigation of the mechanism of functioning of steroid estrogens a series of compounds with unnatural rings junction was synthesized. All investigated compounds exhibit a reduced uterotropic activity. It was established applying the NMR spectroscopy that 7α-methyl-3-methoxy-D-homo-6-oxa-8α,14β-estra-1,3,5(10)-trien-17a-one existed in solution in two conformations distinguished by the structure of the rings B, C, and D simultaneously. The reaction of 17-methylidene-3-methoxy-6-oxa-8α-estra-1,3,5(10)-triene with hydrobromic acid in acetic acid promotes a rearrangement with the migration of a methyl group into the position 17 resulting in the formation of 17,17-dimethyl-6-oxa-8α-gona-1,3,5(10),13(14)-tetraene derivatives.The study of the mechanism of the action of steroid estrogens mediated by their nuclear receptors made it possible to reveal numerous relations between the structure and the biologic properties of this hormone group [1][2][3][4][5], in particular, in the series of estrogens 8α-analogs [6-10]. The formation of an "active" complex between the estrogen α-receptor and the ligands of steroid character requires a precise orientation of the oxygen-containing substituents in the A and D rings with respect to the clusters Glu-353-Arg-394-water and His-524 respectively [11]. Using XRD data on the structure of complexes of various ligands with estrogen receptors it is possible to perform the docking of structures of compounds not yet synthesized into the ligand-bonding sites of the receptors and to predict the hormonal characteristics of these ligands mediated with this receptor [12][13][14][15][16][17][18]. However this approach does not take into account both the conformational plasticity of the receptor and the conformational lability of the ligand.Revealing the ability of a receptor to bind estrogen analogs of uncommon spatial arrangement (in particular, those capable of considerable conformational rearrangements) is necessary for the search of new substances possessing selective biological action. It is no less important to establish the effect on the receptor activation of the signifi cant increase in the distance between the oxygencontaining substituents present at the C 3 and in the region of the D ring of the estrogen 8α-analogs.Compound I is known to exist in the solution in the form of two conformers Ia and Ib (Fig. 1) [19], therefore to solve the desired problem we have chosen for model compound substance II of similar structure.According to ab initio calculations the distance between the oxygen atom at C 3 and the group CH 2 OAc of compound III in the most favorable conformations amounts to 11.3 − 12.4 Å depending on the orientation of the acetyl group; this is considerably more than in the natural estradiol [1] (10.93 Å). Therefore analog III was also included in the group of model compounds (see the scheme).The hydrolysis of compound I [20] followed by the oxidation of the reaction product with Sarett reagent provided compound II. XRD analysis of this analog showed that it existe...