Deacylcortivazol, a potent glucocorticoid with unusual structure and unusual anti-leukemic cell activity.

Abstract

The currently accepted dogma of steroid action states that the structure required for potent glucocorticoid action must at least contain the pregna-4-ene-11β-o1-3,20-dione skeleton. This structure presumably is necessary for the steroid to fit in its binding site on specific glucocorticoid receptors.1,2 This steroid-receptor interaction is widely accepted as the first of a series of molecular events which determine specific steroid-induced cellular reponses.3,4 Bulky substituents on the A-ring have been reported to decrease this activity.1,2,5 We were therefore intrigued to find brief mention in the literature of a group of pyrazolo-steroids with extremely high anti-inflammatory activity despite the presence of bulky A-ring substituents and the absence of the 3-keto group.6–8 Because of this interesting structure we decided to examine this type of steroid for its interaction with glucocorticoid receptors and for its potency as a glucocorticoid. We were able to take advantage of two well-studied tissue culture cell systems available in our laboratory. These have permitted examination of two phenotypically different aspects of glucocorticoid action: a classic hepatic glucocorticoid response, the induction of tyrosine aminotransferase (TAT); and the lympholysis of T-derived leukemic lymphoblasts. Our findings show that these pyrazolo-steroids are extremely potent glucocorticoids and that they bind tightly to glucocorticoid receptors. Our studies also point up the occasional inadequacy of standard cell-free competitive receptor binding assays for demonstrating the proper affinity relationships between steroids. Such assays do not reflect the high potency of the pyrazolo-steroids. However, whole cell binding assays carried out at 37°C more nearly do so, as the data below will show.