Methyl 17β-Carboxyester Derivatives of Natural and Synthetic Glucocorticoids: Correlation Between Receptor Binding and Inhibition of in vitro Phytohaemagglutinin-Induced Lymphocyte Blastogenesis

Publisher Website
Google Scholar
Abstract
Several methyl 17.beta.-carboxyester derviatives of natural and fluorinated glucocorticoids were synthesized to compare their potency to compete for [3H]dexamethasone binding sites in human spleen tumor cytoisols (as a source of large quantities of white blood cells) with their potency to inhibit phytohemagglutinin-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 in the following order: desoximetasone > dexamethasone > corticosterone > cortisol > progesterone > 17-hydroxyprogesterone. The phytohemagglutinin-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.