N-butyl-N-methyl-11-(3′-hydroxy-21′,17′-carbolactone-19′-nor-17′α-pregna-1′,3′,5′(10′)-trien-7′α-yl)-undecanamide:: an inhibitor of type 2 17β-hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic activity

It is well known that 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) play a key role in the formation and inactivation, from circulating precursors, of several active androgens and oestrogens. These enzymes can thus regulate tumoural cell proliferation in androgen- and oestrogen-dependent cancers. Recently, we discovered that adding a spiro-gamma-lactone to the oestradiol nucleus results in a novel inhibitor of type 2 17 beta-HSD, an enzyme that catalyses the interconversions between 4-androstene-3,17-dione and testosterone, and between oestrone and oestradiol. This finding motivated our introducing the spiro-gamma-lactone moiety onto an anti-oestrogenic nucleus. The N-butyl-N-methyl-11-(3'-hydroxy-21',17'-carbolactone-19'-nor-17'alpha-pregna-1',3',5'(10')-trien-7'alpha-yl)-undecanamide (4) was then efficiently synthesized and its biological activity was assessed in vitro. Despite the presence of a bulky alkylamide side chain, the spiro-gamma-lactone function conserved its ability to inhibit type 2 17 beta-HSD (IC50 = 0.35 and 0.25 mu M, with and without side chain, respectively). Furthermore, the selective inhibition by lactone 4 toward type 2 17 beta-HSD (microsomal fraction of human placenta) was demonstrated by the absence of inhibitory activity toward type 1 17 beta-HSD (cytosolic fraction of human placenta). Cell proliferation assays indicated that compound 4 had no oestrogenic activity but did show anti-oestrogenic activity on ER+ cell line ZR-75-1. No androgenic activity could be detected when assayed on the AR(+) cell Line Shionogi either. Based on these facts, we report the synthesis of a new steroidal derivative, one that inhibits type 2 17 beta-HSD while possessing anti-oestrogenic activity. (C) 2000 Editions scientifiques et medicales Elsevier SAS.