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

Abstract

Summary: Several methyl 17ß-carboxyester derivatives of natural and fluorinated glucocorticoids were synthesized in order to compare their potency to compete for [ 3 H]dexamethasone binding sites in human spieen tumour cytosols (äs a source of large quantities of white blood cells) with their potency to inhibit phytohaemagglutinin-induced blastogenesis of normal human peripheral lymphocytes. The 17ß-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 substitütions. The sequence of binding potency is identical compared to that of parent steroids and was found to be in the following order: desoximetasone > dexamethasone > corticosterone > Cortisol > progesterone > 17-hydroxyprogesterone. The phytohaemagglutinin-induced Stimulation of [ 3 H]thymidine incorporation resembles the order of binding potency. The methyl 17ß-carboxyester derivatives of progesterone, 17-hydroxyprogesterone and betamethasone are inactive. The N-benzyl 17ß-carboxamide analogs of dexamethasone and betamethasone behave like their corresponding carboxyesters, suggesting an important influence of the side chain conformation of 17ß-carboxyl derivatives on glucocorticpid receptor binding.

17β-Carboxamide Steroids: Highly Effective Inhibitors of the Phytohaemagglutinin Mediated Blastogenesis of Normal Human Peripheral Lymphocytes

“…This hypothesis, however, assumes that the hormone binding sites of glucocorticoid receptors of different speaes are at least similar (21). On the contrary, we maintain, on the basis of the literature (16,17,22) and our own results (7), that a generalized rationale of structure-activity relationships for glucocorticoid hormones is at the moiiient impossible.…”

“…The benzyl 17ß-carboxamide analogue of dexamethasone (compound Ic) behaved like a glucocorticoid agonist and the order of potency of this agonist was consistent with its affinity for human spieen tumour and rat liver receptors (4)(5)(6)(7).…”

3H-Labelled RU 38486: Characterization of Binding Sites in Human Uterine Cytosol

“…Rat liver and kidney cytosols from adrenalectomized feinale Wistar rats (150-200g) were prepared in the same way äs the uterine cytosol. For HPLC (high performance liquid chromatography) cytosol was prepared in ice-cold Tris/HCl-EDTA-buffer (20 ]RU 38486 together with a 200-ibld molar excess of unlabeled RÜ 38486 or R 5020 ünder identical incubation conditions. All incubations were carried out in triplicate.…”

“…This phenomenon is not general but tissue-specific. Carboxamide derivatives of dexamethasone, for example, are antiglucocorticoids in hepatoma cells (19), but are potent agonists in human peripheral lymphocytes (20).…”

Increase in incorporation into lymphocytesin vitro of esterified anti-inflammatory corticosteroids

“…Recent studies on corticosteroids for skin application has shown that the anti-inflammatory effects of mono-and di-ester derivatives of corticosteroids are more potent than the effects of free corticosteroids [1][2][3]. It is thought that corticosteroid esters having side chains of appropriate length tend to accumulate in skin and that the binding activity of the esters to the receptor is stronger than that of free corticosteroids [3,4].…”