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

Abstract

According to the X-ray diffraction and NMR data, two D-homo-B-nor-8α-analogs of steroidal estrogens in crystal and in solution have similar conformations. The distances between hydrogen atoms in their molecules, calculated ab initio and by the PM3 and MM + methods, correspond to those found experimentally. These results substantiated docking of the modified estrogens into ligand-binding pockets of various estrogen receptor isoforms with a view to search for compounds with improved biological properties. This was demonstrated using 17,17-dimethyl-D-homo-B-nor-8α-estrone as an example.Total syntheses of modified analogs of steroidal estrogens with cis-junction of the B and C rings, which exhibit improved biological properties, include at least 10-15 steps [1]. Therefore, the possibility of predicting at least some properties of the targeted compounds is important. In the present article we propose a new approach to preliminary estimation of hormonal activity of D-homo-B-nor-8α analogs of steroidal estrogens mediated by the corresponding nuclear receptors.It is known that B-nor-8α analogs of steroidal estrogens exhibit much weaker uterotropic activity than do steroids with six-membered B ring [1]. On the other hand, they can retain other biological properties intrinsic to natural hormones. For example, 16,16-dimethyl-D-homo-B-nor-8α-estrone shows immune-suppressing activity, whereas uterotropic action is absent [1]. 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.Compound II was synthesized as shown in Scheme 1. The syntheses of intermediate products III-VIII involved no difficulties, and the yields in all steps were consistent with published data for analogous reactions [1,7]. However, catalytic hydrogenation of estrapentaene VIII, followed by oxidation, gave compound II in a yield not exceeding 29%, and factors responsible for the poor yield of II are not clear.The steric structure of steroid II in crystal and in solution was determined by X-ray analysis and NMR spectroscopy, and the experimental data thus obtained were compared with the results of ab initio molecular modeling (6-31G basis set) and semiempirical PM3 and MM + calculations [8]. According to the X-ray dif-

Naturally Occurring Norsteroids and Their Design and Pharmaceutical Application

“…From the roots of Ziziphus jujuba, a cytotoxic compound, 2,28-Dinor-24-hydroxylup-1,17 (22)-dien-27-oic acid (127), was discovered [88][89][90]. Jingullic acid (128), another noteworthy compound, was found in the bark of Emmenosperma alphitoniodes [91].…”

“…This research branch focuses on the ocean's biodiversity for novel compounds that could lead to new or improved pharmaceuticals. Marine ecosystems' unique conditions often produce structurally distinctive and biologically potent compounds not found in terrestrial environments [41,42,[126][127][128][129]. From the methanolic extract of the starfish Astropecten polyacanthus, four steroids named astropectenols A-D were identified, but only astropectenol A (189, structures in Figure 7) possesses a B-nor skeleton.…”

“…This research branch focuses on the ocean's biodiversity for novel compounds that could lead to new or improved pharmaceuticals. Marine ecosystems' unique conditions often produce structurally distinctive and biologically potent compounds not found in terrestrial environments [41,42,[126][127][128][129].…”

Naturally Occurring Nor-Steroids and Their Design and Pharmaceutical Application

“…From the roots of Ziziphus jujuba, a cytotoxic compound, 2,28-Dinor-24-hydroxylup-1,17( 22)dien-27-oic acid (127), was discovered [90]. Jingullic acid (128), another noteworthy compound, was found in the bark of Emmenosperma alphitoniodes [91].…”

New analogs of steroid estrogens

“…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.…”