Synthesis and investigation of the biological properties of 6-oxa-8α-analogs of steroid estrogens containing a methyl group at C-4 (original) (raw)
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Approaches for Searching of Modified Steroid Estrogen Analogues with Improved Biological Properties
Steroids - Basic Science, 2012
Steroids-Basic Science 172 the treatment of oncological estrogen-sensitive diseases, cardio-vascular system, osteoporosis, neuroendocrinal diseases. The division of agents on such groups has relative character, because the activity of steroid estrogens has multifunctional character and one compound may be effectively used in various fields. This is a main reason why modified steroid estrogens have the advantage in comparison with huge number of heterocyclic compounds, having more selective action. Obviously that most perspective search of such compounds is done on the basis of knowledge about estrogen action mechanism, particularity of its structure and metabolism. Several authors consider that main fast non genomic effects of estrogens are mediated by their membrane receptors (Levin, 2002; Sak & Evaraus, 2004). Experimental data about the identity of nuclear and membrane ER in MCF7 cell are presented in the publication (Pedram et al., 2009). Obviously, ligand specificity may be significantly different. Mechanisms of membrane receptors action are still unclear, very often it is not proved that one or another effect is mediated by namely this group of receptors (Warner & Gustafsson, 2006). The absence of data about ligand specificity to membrane receptors does not allow to plan the synthesis of modified steroids with selective action, especially taking into account that their activity is realizing on many ways. During the consideration of osteoprotective action of estrogens and its influence on processes of cardio-vascular system we restrict ourselves to state the facts, because the decision concerning the synthesis of potential agents is usually reached on the analogy with known compounds.
Russian Journal of General Chemistry, 2011
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 1 H 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. 9β-Analogs of steroidal estrogens are characterized by modified spectrum of biological activity as compared to the corresponding natural compounds [1-3]; they are also used as intermediate products in the synthesis of 9β,10α-androgen [4] and 9β,10αprogestagen derivatives [5]. Biological properties of Bnor-9β-estrogens are almost unknown. 18-Methyl-Dhomo-B-nor-9β-estrone was reported to exhibit antiatherosclerotic effect, whereas its uterotropic activity was completely absent [6, 7]. The latter is very important, for in most cases hormone action of estrogens is related to their cancerogenic effect [8].
Synthesis and receptor-binding examination of 16-hydroxymethyl-3,17-estradiol stereoisomers
2002
The four 16-hydroxymethylestra-1,3,5(10)-triene-3,17-diol isomers were synthesized and tested in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities are lower than 2.0% relative to that of the reference molecule estra-1,3,5(10)-triene-3,17-diol. The affinities of the tested compounds for the androgen and progesterone receptors are very low (K i Ͼ 100 m and 1 M, respectively). The prepared 16-hydroxymethylestra-1,3,5(10)-triene-3,17-diol isomers are therefore estrogen receptor-selective molecules.
The Synthesis and Properties of B Nor8-Isoanalogues of Steroid Estrogens
Russian Journal of Bioorganic Chemistry
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.
Biological activity of novel progesterone derivatives having a bulky ester side chains at C-3
Steroids, 2008
s t e r o i d s 7 3 ( 2 0 0 8 ) 838-843 a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / s t e r o i d s Bulky ester side chains steroids Mibolerone a b s t r a c t Antiandrogens are widely used agents for the treatment of androgen dependent diseases as inhibitors of androgen receptors (AR) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of the structure of the ligand in relation with the nuclear co-repressors. In the present study, we investigated the relationship between log P (the partition coefficient) of four pregnane derivatives 9a-9d and their biological activity. For this purpose, we determined the relative binding affinity (RBA) of steroids 9a-9d to androgen receptor (AR) obtained from rat prostate cytosol, using labeled mibolerone (MIB) as ligand. The IC 50 value of each compound was calculated according to the plots of concentration versus percentage of binding. The in vivo effect of 9a-9d was determined on the weight of the prostate and seminal vesicles from castrated hamsters treated with dihydrotestosterone.
Steroids, 2003
D-Homo derivatives in the androstane and estrane series, 12-19, were synthesized by a fragmentation-cyclization reaction of 16-oximino-17-hydroxy-17-substituted derivatives 3-9, or by cyclization of the corresponding D-seco derivatives 20-26. The structures were confirmed by X-ray analysis of compounds 12 and 16. Preliminary assessment of inhibitory effects of D-homo derivatives from androstane series towards aromatase, 3-hydroxysteroid dehydrogenase (3-HSD), 17␣-hydroxylase/C17-20 lyase (P450c17) and 17-HSD indicated much lower inhibitory potential compared to previously tested activity of another type of D-modified steroids, namely D-seco derivatives. Also, assessment of potential antiestrogenic activity of derivatives from estrane series showed absence of such an activity.