Methyl 17 beta-carboxyester derivatives of natural and synthetic glucocorticoids: correlation between receptor binding and inhibition of in vitro phytohaemagglutinin-induced lymphocyte blastogenesis.

Several methyl 17 beta-carboxyester derivatives of natural and fluorinated glucocorticoids were synthesized in order to compare their potency to compete for [3H]dexamethasone binding sites in human spleen tumour cytosols (as a source of large quantities of white blood cells) with their potency to inhibit phytohaemagglutinin-induced blastogenesis of normal human peripheral lymphocytes. The 17 beta-carboxylic acids neither show binding activity nor inhibition of blastogenesis. Methylation partially restores the binding capacity and the intensity of this effect depends on the kind of ring substitutions. The sequence of binding potency is identical compared to that of parent steroids and was found to be in the following order: desoxymethasone greater than dexamethasone greater than corticosterone greater than cortisol greater than progesterone greater than 17-hydroxyprogesterone. The phytohaemagglutinin-induced stimulation of [3H]thymidine incorporation resembles the order of binding potency. The methyl 17 beta-carboxyester derivatives of progesterone, 17-hydroxyprogesterone and betamethasone are inactive. The N-benzyl 17 beta-carboxamide analogs of dexamethasone and betamethasone behave like their corresponding carboxyesters, suggesting an important influence of the side chain conformation of 17 beta-carboxyl derivatives on glucocorticoid receptor binding.