Synthesis and steroid sulphatase inhibitory activity of C19-and C21-steroidal derivatives bearing a benzyl-inhibiting group

Two series of compounds, benzyl alkylated at position 17 alpha and 20 of an drostane and pregnane, respectively, were synthesised and tested for steroi d sulphatase inhibition. We compared the ability of the compounds to inhibi t steroid sulphatase obtained from two different sources (homogenates of tr ansfected HEK-293 cells and Jeg-3 cells) and with two types of substrate (D HEAS or E1S). The inhibitory activity of 17 alpha -benzyl-5 alpha -androsta ne-3 beta ,17 beta -diol (7), 17 alpha -benzyl-5-androstene-3 beta ,17 beta -diol (9), 17 alpha -benzyl-4,17 beta -dihydroxy-4-androsten-3-one (15) an d 20-benzyl-5-pregnene-3 beta ,20 alpha -diol (16) has proven to be superio r to that of danazol, the first steroid sulphatase inhibitor to be reported , but still lower than that of the potent inhibitor estrone-3-O-sulphamate. The inhibitory activity of compound 7 was as potent as that of its previou sly reported estrane analogue, 17 alpha -benzyl estradiol. Benzyl alkylated compounds with no OH group on the A-ring (with a 4-OCH3, 4-Cl, or 4-H and their precursor epoxides), as well as a series of basic steroids without a benzyl group (ADT, epi-ADT, 3 alpha -diol, 3 beta -diol, DHEA, Delta (5)-di ol, DHT, T, Preg and Prog), did not show steroid sulphatase inhibition. We have thus demonstrated that the steroid sulphatase inhibitory effect of a b enzyl group, previously observed for an estrane nucleus, can be extended to certain androstane and pregnane nuclei bearing a 3 beta -OH or a 4-OH grou p. Inhibitors 7, 9, 15 and 16 did not induce any proliferative effect on an drogen-sensitive Shionogi cells. However, when tested on oestrogen-sensitiv e ZR-75-1 cells, a proliferative effect was observed for 7 and 9, but not f or 15 and 16. (C) 2001 Editions scientifiques et medicales Elsevier SAS.