Alexander Kasal

Brassinosteroids: synthesis and activity of some fluoro analogues.

Three types of 5alpha-androstane and ergostane analogues of brassinolide, containing a fluorine atom in either the 3alpha or the 5alpha positions or in 3alpha and 5alpha positions, were prepared using standard operations (reaction of 3beta-alcohols with (diethylamino)sulfur trifluoride, cleavage of epoxide with HF in py or BF 3.Et 2O). The 5alpha-fluorine was found to affect chemical reactivity (e.g., electrophilic addition to the Delta (2)-double bond) as well as physical properties (e.g., NMR, chromatographic behavior) of the products. Cytotoxicity of the products was studied using human normal and cancer cell lines with 28-homocastasterone as positive control and their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard. The equivalence of F and OH groups was observed in some of the active compounds. The anticancer and the brassinolide-type activity do not correlate with each other: ergostane derivatives were most active in the former test while androstane derivatives were best in the latter.

On steroids CIII. Molting deficiencies produced by some sterol derivatives in an insect (Pyrrhocoris apterus L.)

Abstract Several sterol derivatives have been found to inhibit the postecdysial hardening and sclerotization of the cuticle in Pyrrhocoris . These compounds are derivatives of cholestane and 24βF-methylcholestane containing 3β-hydroxy and 6-keto groups. It is assumed that these compounds may have ecdysone-antagonistic action.

Steroids with modified ring A or B: Screening for potential antiandrogenic and synandrogenic activity

Abstract A series of 14 steroids with modified ring A or B (A-homosteroids, B-homosteroids and 3,6-cyclo-A-nor-3,5-seco-6β-androstanes) were tested for potential antiandrogenic activity by binding assays, using prostate cytosol receptor or sex hormone binding globulin as binder, and by the inhibition of 5α-reductase. The results of in vitro screening were compared with in vivo bioassay. The antiandrogenic or synandrogenic activity of these compounds seemed to have an integrated effect on steroid binding to the cytosol receptors, displacement of the endogenous androgens from the binding to sex hormone binding globulin and influence the transformation of testosterone into 5α-dihydrotestosterone.

Some reactions of 16α,17α-oxido-5α-cholestane derivatives, synthesis of 17α-hydroxycholest-4-en-3-one

Abstract Careful epoxidation of the Δ16-olefins 3 and 4 yielded 16α,17α-epoxides 5 and 6 which were reduced by lithium aluminium hydride, oxidized, and dehydrated to 17α-hydroxycholest-4-en-3-one 20, i.e., an epitestosterone homolog containing a well tolerated alkyl group at position 17. Under catalysis of acids, epoxide 5 was rearranged to Δ13-16α-alcohol 10. Less careful epoxidation of Δ16-olefin 4 with excess of peroxy acid led to products of double epoxidation (i.e., epoxidation, rearrangement, and another oxidation) 7 and 12. Structures of products of rearrangement were studied mainly by NMR spectroscopy. (Steroids 59: 335–340, 1994)

Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) Derivatives with a Polar Chain in Position 16α: Synthesis and Activity

The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by previously prepared allopregnanolone with a 16alpha-bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16alpha with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [(35)S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABA(A) receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain.

Steric effects on NMR chemical shifts controlled by the solvent's accessible surface

Steric effects observed on 29Si NMR chemical shifts in trimethylsiloxysteroids are chiefly due to hydrogen bonding which is controlled by solvent accessibility of the oxygen atom in the molecule.

Analytically significant steric effects on 29Si NMR chemical shifts as observed in trimethylsilylated steroids

Abstract 29 Si NMR chemical shifts were measured in four trimethylsilylated stereoisomers of 3ξ-hydroxy-5ξ-cholestane. The chemical shifts obtained in dilute deuteriochloroform solutions fall into two distinct ranges one around δ 13.2, indicative of axial position of the trimethylsiloxy group on the cyclohexane ring, and the other around δ 14.9 ppm.

Antihormonal properties of some new A-homo-B, 19-dinor steroids of the androstane series

On solvolysis of Westphalen-type steroids with a leaving group in the position 6 beta (e.g., 2), products of elimination (followed by rearrangement and fragmentation of the steroid skeleton) were prepared (e.g., 4 and 5). These products were subsequently converted to suitable analogs of the compound, which has been reported to promote hair growth (1). Compounds 11 to 13 exhibited strong antiandrogenic activity in vivo; however, this activity could not be interpreted either in terms of inhibition of 5 alpha-reductase or by strong binding to an androgen receptor.

Preparation of antiandrogenic 17-hydroxy-3,6-cyclo-4-nor-3,5-seco-6β-androstan-3-one by deoxygenation of the corresponding 5-hydroxy derivatives

This paper reports on three alternative procedures for the preparation of antiandrogenic 17β-hydroxy-3,6-cyclo-4-nor-3,5-seco-6β-androstan-3-one 15. The key step represents the removal of the oxygen functional group from position 5 which was effected by radical deoxygenation of thioesters of type 13. The variant of choice was the deoxygenation of the 5-thioimidazolide 29 prepared from diketone 5. The 3-keto group was selectively protected during hydride reduction by conversion into the corresponding silyl enol ether.

Progesterone side-chain degradation beside hydroxylation with Rhizopus nigricans depends on the presence of nutrients

In the absence of nutrients, Rhizopus nigricans transforms progesterone into a mixture of 11 alpha-hydroxy-4-androstene-3,17-dione and 11 alpha-hydroxy-1,4-adrostadiene-3,17-dione. The same mixture is obtained by the transformation of testosterone and its acetate.