Molecular mechanics and X-ray crystal structure investigations on conformations of 11 beta substituted 4,9-dien-3-one steroids.

The influence of 11 beta-phenyl substitution upon 4,9-dien-3-one steroid-backbone conformations is calculated by means of the MM2p molecular mechanics scheme. In the case of steroids having a 13 beta configuration, the lowest strain energy is always evaluated for the conformational combination of rings A(inverted) B(normal) while, moreover, the 11 beta substitution increases the relative stability of the conformation A(normal) B(normal) compared to the nonsubstituted compound. Introduction of the 11 beta substituent causes some bowing of the energy-minimum structures in the A-ring region toward the beta side. For 13 alpha configurated steroids, the ring conformations A(inverted) B(normal) C(boat) and A(normal) B(inverted) C(twist/boat) are found to be energetically preferred. Quantitative description of different ring conformations using asymmetry and pseudorotational parameters as well as the comparison of molecular mechanics and available X-ray structure data give an impression of the conformational mobility. Whereas the effect of 11 beta substitution within a given ring conformation is limited, contributions to molecular flexibility can be found in the ability to adopt different basic conformations and in the occupation of near-minimum structures. An X-ray crystal structure analysis of a potential antiprogestational steroid has been performed, and the results are in good agreement with the calculated structure.

MTD calculations on quantitative structure-activity relationships of steroids binding to the progesterone receptor.

The minimal topological difference (MTD) method is used to describe quantitative structure-activity relationships (QSAR) for the progesterone-receptor binding affinity including 59 progestational steroids. Multiple correlation coefficients of r = 0.962 and r = 0.955 are obtained by use of the MTD variable and a measure of hydrophobicity for the series of progesterone and ethisterone derivatives, respectively. Hydrophobic effects are found to strongly influence receptor binding. In accordance with the hydrogen bonding concept, the optimized MTD receptor maps indicate cavity vertices in the regions of oxygen functions at C3 and in the 17 beta position. Receptor wall vertices are attributed in the areas of 4, 10 beta, and 13 beta substituents of 4-en-3-one steroids while 17 alpha side chains additionally contain receptor cavity vertices. A comparison of corresponding receptor maps suggests in accord with X-ray crystal structure data that progesterone and ethisterone derivatives are bound in somewhat different orientations relative to the receptor surface.

Quantitative structure-activity relationships of estrogenic steroids substituted at C14, C15.

The uterotropic activity of thirty 3-methoxyestradiol derivatives is measured and discussed on the basis of X-ray crystallographic results and quantitative structure-activity relationship analyses involving hydrophobic substituent constants pi and f as well as steric parameters Pr and L. In addition, estrogenicity is compared to data of interceptive activity and receptor binding affinity. All the biological data exhibit a high degree of intercorrelation. 17 beta-Hydroxysteroids having 14 alpha configuration reveal a generally better capability of high-affinity binding than those being 14 beta configurated. Between the uterotropic activity and the hydrophobicity of C14, C15 substituents, statistically significant correlations are found which suggest a close contact between the steroidal D-ring subsite and the receptor protein (e.g. for 14 alpha steroids: log UDD = -0.996 pi -0.392; n = 9, r = -0.943, s = 0.235, t = -7.5, alpha less than 0.001). The hydrophobic nature of both 14 alpha and 14 beta medium-sized substituents employed is shown by QSAR regressions to exert a stronger influence than steric effects. Furthermore, there are indications to additional hydrogen bonding and steric repulsion phenomena. As to the receptor-binding models discussed in the literature, it is concluded that the receptor protein has a high conformational flexibility to accommodate very different drug structures all having the common phenolic ring A. But, if an appropriate spacing of steroidal key atoms is recognized by the receptor and, consequently, the steroid-receptor complex is formed, the binding is complemented by hydrophobic interactions also in the D-ring region.

Action of cholestane-3 beta,5 alpha,6 beta-triol on rats with particular reference to the aorta.

Cholestane-3 beta,5 alpha,6 beta-triol, administered orally to rats in different doses and for varying lengths of times, effected toxic cell damage on aortic smooth muscle cells and endothelium. Cholesterol, applied in the same doses, did not lead to appreciable alterations of the aorta. After parenteral application of lipids with simultaneous administration of cholestane-triol there were no demonstrable fat deposits in the damaged aortic wall with angiotensin II (AII) induced hypertension. Thus, there was no recognizable influence of hypertension on increased fat passage in the arterial wall, or any action of lipids to enhance the permeability of vessels. However, the hypertension had an exacerbating effect in so far as in animals with AII-induced blood pressure rise alterations of the media were more pronounced after cholestane-triol, although we were unable to rule out a primary effect of AII. A potentiation of the cholestane-triol action by simultaneous application of cholesterol demonstrated for the rabbit did not occur in rats. Blood content was lowered mostly by cholestane-triol, also by cholesterol. HDL-cholesterol was little affected; almost no influence was observed in triglycerides. The strong cytotoxic action of cholestane-triol underlines its health-damaging role. Due to its action on the aorta of the rat, despite the animal's resistance to arteriosclerosis, involvement of this cholesterol derivative in the pathogenesis of arteriosclerotic alterations can not be excluded.

Quantitative structure-activity relationships of cardiotonic steroids using empirical molecular electrostatic potentials and semiempirical molecular orbital calculations.

Empirical molecular electrostatic potentials and a rigid receptor H atom model are used to calculate differences in the interaction energy of cardiotonic steroids with the digitalis receptor. An attempt is made to map the receptor H binding sites for two different steroid conformations with respect to 17 beta side-chain orientation. The calculated interaction energies using single-crystal X-ray structure data indicate linear relationships with the Na+, K+-ATPase inhibitory activity. On the basis of these correlations, the activity of 8 so far pharmacologically not investigated steroids containing C = O in 17 beta substituents are estimated with the help of structural data determined by means of the semiempirical CNDO molecular orbital theory.

Long-acting contraceptive agents: aliphatic and alicyclic carboxylic esters of levonorgestrel.

Esters of levonorgestrel (13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) with a variety of aliphatic and alicyclic carboxylic acids have been prepared and characterised. In tests for the suppression of estrus in rats, esters with short-chain aliphatic acids and with cyclobutane-carboxylic acid were considerably more active than the standard, norethisterone enanthate (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one). Such esters show great promise for development as long-acting progestogens.

The synthetic approach to STS 557 - structure activity relationships in 17 alpha-CH2X-substituted 19-nortestosterone derivatives.

The synthesis of 17 alpha-CH2X-substituted 19-nortestosterone derivatives (X = halogen, CN, N3, OH, NH2 etc.) is described. Starting with 1,4-dihydroestradiol 3-methyl ether the 17 alpha-CH2X-17 beta-hydroxy-moiety was introduced via a 17 beta-spiroepoxide which could be cleaved with various nucleophilic agents giving the desired derivatives. In the McPhail assay with immature rabbits some of these substances showed good progestagenic activity on oral administration. The influence of structural modifications on the activity is discussed. The best effect is observed if an additional double bond is introduced in position 9(10). While the 19-nortestosterone derivative with X = CN has only an activity of about 20% of that of norethisterone acetate, the introduction of a second double bond leads to a compound (STS 557) which has an oral potency more than ten times as high as levonorgestrel.

[Synthesis and serum cholesterol-lowering and uterotropic effects of 15,16,17-trisubstituted oestratriene 3-methyl ethers. Part 63: On steroids (author's transl)]. / Synthese, serumcholesterolsenkende und uterotrope Wirkung von 15,16,17-trisubstituierten Ostratrien-3-methylethern. 63. Mitteilung: Uber Steroide.

The preparation of the 17 beta-carbamoyl derivatives 4 and of the 17 beta-carbonic acid esters 5 from 15 beta,16 beta-epoxy-3-methoxyoestra-1,3,5(10)-triene-17 beta-ol (3a), and the subsequent opening of the 15 beta,16 beta-epoxy group resulting in 15 beta,16 alpha,17 beta-trisubstituted oestratrienes 6 are described. The influences of several substitutents in the positions 15 and 16 and of the 17 beta-hydroxy group and derivatives thereof on the uterotropic and cholesterol-lowering activities were investigated in rats after oral application. A correlation between the cholesterol-lowering and the uterotropic activity could be established. Activity dissociation was not achieved.

[A new class of highly active progestagens: 17 alpha-CH2X-substituted gona-4,9(10)-dienes. 58. Steroids]. / Eine neue Klasse hochwirksamer Progestagene: 17 alpha-CH2X-substituierte Gona-4,9(10)-diene. 58. Mitteilung: Steroide.

The synthesis of new gona-4,9(10)-dienes with a 17 alpha-CH2X-substituent (X = CN, N3, Cl or Br) is described. The progestagenic activity of these substances was studied in the McPhail assay using immature rabbits. The compound XVI (X = CN, STS 557) is the most potent one, showing an activity about ten times higher than D-norgestrel. Differences in the activity caused by different routes of application are discussed.

[Postcoital contraception in primates. I. Action mechanism of a potential postovulatory fertility-inhibiting substance STS 456 in the baboon (Papio hamadryas)]. / Postkoitale Kontrazeption bei Primaten. I. Zum Wirkungsmechanismus einer potentiellen postovulatorisch fertilitätshemmenden Substanz STS 456 beim Pavian (Papio hamadryas)

With the substance STS 456, an estrogenic active steroid, a high fertility inhibition could be obtained in the pavian, when administered p. o. over a 5 day period postcoital. The effectiveness and also the side effects were dose dependent. The antifertility mechanism is based on an luteolytic effect, demonstrated by analytical hormonal investigations. The inhibition of the synthesis of steroids in the ovary affected not only progesterone but also the estrogens.

[Chromosome analysis in baboons born following the use of potential, postovulatory, fertility-inhibiting steroids]. / Chromosomenanalytische Untersuchungen der nach der Anwendung potentieller postovulatorisch-fertilitätshemmender Steroide geborenen Paviane.

The chromosomal aberrations of the offsprings of four mothers of pavians which received the steroid substances STS 456 and J 628 postcoitally were investigated. The aberration rate was within the norm. Malformation of the offsprings did not occur.

[Postcoital contraception in primates. II. Examination of STS 153 and STS 287 as interceptives in the baboon (Papio hamadryas)]. / Postkoitale Kontrazeption bei Primaten. II. Prüfung von STS 153 und STS 287 als Interzeptiva beim Pavian (Papio hamadryas).

The interceptive activity of 2 new synthesized steroid compounds: STS 153 (17 beta-Phenylaminocarbonyloxy-estra-1,3,5(10)-triene-3-methyl ether and STS 287 (16 alpha-Bromo-17 beta-[N',N'-dimethylhydrazino]-carbonyloxy-estra-1,3,5(10)-triene-3-methyl ether) and of 17 alpha-Ethynylestradiol was investigated in baboons.--Postcoital oral administration of 1--3 mg/kg b. w. STS 153 for 5--7 days and of 1 mg/kg b. w. STS 287 for 5 days resulted in a fertility inhibition of about 90% and 95% respectively. A dose of 2 mg/kg b. w. of ethynylestradiol was necessary to attain complete fertility inhibition. Following administration of STS 153 and STS 287, side effects were not observed. Pharmacokinetic aspects are discussed.