New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects

BURTON, GERARDO

Atenas, Grecia

Congreso; 12th International Congress on Hormonal Steroids and Hormones and Cancer; 2006

(Conferencia Invitada): Antiglucocorticoids (antiGC) that act as antagonists at the GR level may be used to block or modulate the undesirable effects of GC excess  (from endogenous or exogenous origin). The search for an antiGC resulted in RU-486 in the early 80’s, also a potent antiprogestin and abortifacient. Subsequent developments were mostly focused in derivatives with antiprogestin activity and free of antiGC activity. Although the need for a pure antiGC persisted, work in this direction generally used RU-486, with its bulky aromatic substituent at C-11, as a lead. Further on, in view of the variety of physiological processes in which GCs are involved, selective antiGCs that can block only some of these processes (eventually with tissue specificity) would be highly desirable. Our approach started from the observation that the introduction of a 6,19-epoxy bridge in the progesterone molecule led to a bent structure at the A/B ring junction devoid of MC and GC activity. Introduction of a 21-hydroxyl in the latter molecule resulted in a GR antagonist still with no affinity por MR and PR. Antagonistic activity was evidenced by partial blocking of dexamethasone induction of TAT and thymocyte apoptosis. Taking this compound as a lead, we replaced the oxygen bridge by a sulfur bridge to give a less bent, more flexible molecule. 21-hydroxy-6,19-Epithioprogesterone exhibited improved antiapoptotic activity on thymocytes but was less effective blocking TAT induction. This selectivity was improved further by oxidation to the sulfone. The sulfone but not the reduced compound also reverted dexamethasone-mediated inhibition of NFkB activity in Hela cells. Blocking of the apoptotic effect of TNFa by dexamethasone in L929 cell line (mouse fibroblasts) was reverted partially, only by the sulfone which exhibited mild agonistic/antagonistic activity in this assay. The sulfoxide only had agonistic activity. None of these compounds showed antiprogestin activity. A similar overall molecular shape but less lipophylic and with higher metabolic stability was attained by introduction of a methylene bridge (6,19-methanoprogesterone). More recently we have synthesized a highly bent steroid with a direct bond between C-6 and C-19 (6,19-cycloprogesterone and its 21-hydroxy derivative). This structure showed affinity for GR.