Eszter Meskó

In vitro inhibitory effects of 16-methyl-substituted steroids on 5α-reductase in rat and human prostates

The inhibitory effects (IC50) of 16-methyl steroids on 5 alpha-reductase were studied. The in vitro experiments were carried out with homogenates of rat and human prostates. The investigated 16-methyl steroids were found to be weak inhibitors. In comparison with the known 5 alpha-reductase inhibitor 4-MA, the relative IC50 values of the studied compounds are 4.7 times or more greater than 4-MA in human prostate and 23.5 times or more greater than 4-MA in rat prostate. The IC50 values increase in the sequence 16 alpha, 16-beta- and 16,16-dimethyl derivatives. In human prostate homogenates IC50 varies between 0.6 and 120, while in rat it ranges from 1.6 to 1000 microM. This shows that the enzyme of the human prostate is more sensitive than that of the rat prostate to the methyl-substituted compounds. Acylation of the 17-hydroxy group significantly increases the IC50 values (cf. 8,11: from 4.8 to 23.5 and from 0.52 to 0.62;9,12: from 26.0 to 170.0 and from 0.58 to 1.4;15,17: from 3.9 to 35.0; and 16,18: from 5.6 to 58.0 microM). Whereas lack of a 19-CH3 group improves the inhibitory effect in the 16-unsubstituted compounds (1,19;14,22), the reverse hold in the 16-methylated derivatives (9,20; 10,21; 15,23; 16,24).

Steroids 35: Synthesis of 16,16-dimethyl-17β-hydroxysteroids

Abstract The reaction of 16-methylene-17-ketosteroids (Ia), (Ic) and (Ie) with methyl magnesium iodide yields 16-methylene-17α-methyl-17β-hydroxysteroids (IIa), (IIb) and (IId). These are subjected to the addition of hypobromous acid and the subsequent anionotropic rearrangement to convert them into 16α-methyl-16β-bromomethyl -17-ketosteroids (Va), (Vb) and (Vd). These were reduced with LiAlH 4 to obtain 16,16-dimethyl-17β-hydroxysteroids (VIa), (VIb) and (VId). Compounds (VIIa) and (VIIe) were selectively deacetylated yielding (VIIb) and (VIId); these were then oxidized and hydrolyzed to convert them into (VIf) and (VIg).

Steroids. Part 32. Configurational analysis of 16-methyltestosterone derivatives

The four possible isomers of 16-methylandrost-5-ene-3β,17-diol (1)–(4) have been converted into the corresponding 17-hydroxy-16-methylandrost-4-en-3-ones (5)–(8). The steric structures of the resulting epimers have been determined by 13C and 1H n.m.r. spectroscopy; thereby the exact configurational correlation of several 17-hydroxy-16-methylandrost-4-en-3-ones, reported in the literature, have been established.

In vitro binding of 16-methylated C18 and C19 steroid derivatives to the androgen receptor

The binding of androgens and structurally related analogues to the androgen receptor was studied. The in vitro experiments were carried out with cytosol of castrated rat prostate, using [3H]R1881 (methyltrienolone) as radioligand. The binding parameters measured were Kd = 1.25 x 10(-10) M and Bmax = 111 fmol (mg protein)-1. Ligand specificity was confirmed by competition experiments with known androgen, oestrogen and progestogen ligands. The receptor binding of substituted steroids was studied. The RBAs (relative binding affinities) of our recently synthetized 16-alkyl steroids were low. The only exception was the 17 beta-hydroxy-16 beta-methylestr-4-en-3-one, which exhibited the remarkable RBA of 22.9%.