ABSTRACT
Starting from D-seco derivatives of 5-androstene 1-3, the D-homo lactones, 4 and 5, were synthesized. By the Oppenauer oxidation and/or by dehydration of 4 and 5 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil), the corresponding D-lactones 6-12 were obtained. The structures of 6 and 10 were unambiguously proved by the appropriate X-ray structural analysis. Anti-aromatase assay showed that tested compounds possess inhibition potency, however, two to four times smaller (IC50 from 0.2 to 0.7 microM, respectively) in comparison to aminoglutethimide (AG).
Subject(s)
Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/pharmacology , Lactones/chemical synthesis , Lactones/pharmacology , Steroids/chemistry , Animals , Aromatase Inhibitors/chemistry , Female , Lactones/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Rats , Spectrophotometry, InfraredABSTRACT
The title compounds, C22H31NO3 and C20H27NO2, have similar conformations except in the molecular geometry and the bonding of two of the rings. These differences lead to marked differences in the biological activities of these compounds. Molecules of both compounds are linked by weak C-H...O hydrogen bonds in the crystal structures.
Subject(s)
Androstenes/chemistry , Aromatase Inhibitors/chemistry , Nitriles/chemistry , Androstenes/pharmacology , Aromatase Inhibitors/pharmacology , Crystallography, X-Ray , Hydrogen Bonding , Molecular Conformation , Molecular Structure , Nitriles/pharmacology , Structure-Activity RelationshipABSTRACT
The starting compound for synthesis of new 16,17-seco-estratriene derivatives was 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5(10)-triene-16-nitrile (1b), obtained from estrone in several synthetic steps. 17-Tosyl, -chloro-, bromo-, and -iodo- derivatives 2b, 4b, 5b, and 6b were prepared directly from secocyanoalcohol 1b, while the 17-fluoro-derivative 3b was obtained from tosylate 2b in the reaction with tetrabutyl ammonium fluoride. The corresponding 3-hydroxy derivatives of these compounds were produced by action of hydrogen in presence of Pd/C, except the 3-hydroxy-17-iodo derivative 6a, which was obtained from 3-hydroxy-17-tosyloxy derivative 2a. All the newly synthesized compounds in biological tests on experimental animals exhibited an almost total loss of estrogenic activity, while most of them even prevented the action of endogenous estrogens. On the other hand, most of them, except compounds 3a and 6b, partially hindered the action of estradiol benzoate, behaving as moderate antagonists.
Subject(s)
Estrenes/pharmacology , Estrogen Antagonists/pharmacology , Secosteroids/pharmacology , Animals , Crystallography, X-Ray , Drug Evaluation, Preclinical , Estrenes/chemical synthesis , Estrogen Antagonists/chemical synthesis , Estrogens/chemical synthesis , Estrogens/pharmacology , Female , Organ Size/drug effects , Rats , Secosteroids/chemical synthesis , Structure-Activity Relationship , Tamoxifen/pharmacology , Uterus/drug effects , Uterus/growth & developmentABSTRACT
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 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17 alpha-hydroxylase/C17-20 lyase (P450c17) and 17 beta-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.
Subject(s)
Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Homosteroids/chemical synthesis , 17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Androstenes/chemistry , Androstenes/pharmacology , Animals , Aromatase Inhibitors , Enzyme Inhibitors/pharmacology , Estranes/chemistry , Estranes/pharmacology , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor Modulators/chemistry , Estrogen Receptor Modulators/pharmacology , Homosteroids/chemistry , Homosteroids/pharmacology , Leydig Cells/enzymology , Male , Molecular Structure , Rats , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
The title molecule, C(26)H(30)O(3), shows a novel chemical rearrangement of the substituents at position 17, i.e. an alpha-orientation of the hydroxy group and a beta-orientation of the bulky benzyl moiety. The packing arrangement consists of coils formed by O(2)...O(3) hydrogen bonds along the c axis. The compound shows complete loss of oestrogenic activity, and neither does it exhibit an antagonistic effect.
Subject(s)
Estradiol Congeners/chemistry , Estrone/chemistry , Estrone/analogs & derivatives , Hydrogen Bonding , Models, Molecular , Molecular ConformationABSTRACT
The two title 16,17-secoestrone derivatives, 3-methoxy-17-oxo-17-phenyl-16,17-secoestra-1,3,5(10)-triene-16-nitrile, C(25)H(27)NO(2), (I) (17-oxo substituent), and 17-hydroxy-3-methoxy-17-phenyl-16,17-secoestra-1,3,5(10)-triene-16-nitrile, C(25)H(29)NO(2), (II) (17-hydroxy substituent), have quite different conformations in the solid state. These conformational differences can be minimized by molecular mechanics calculations. Thus, the remarkable difference in the biological activity of the two compounds, e.g. the strong oestrogenic characteristics of (I) and the moderate antioestrogenic action of (II), must be caused by the difference in substitution at C17. In (II), the molecules are linked by O-H...N hydrogen bonds, forming spirals along the b direction.
