3Beta-sulfamate derivatives of C19 and C21 steroids bearing a t-butylbenzyl or a benzyl group: synthesis and evaluation as non-estrogenic and non-androgenic steroid sulfatase inhibitors.
A series of C19 and C21 steroids bearing one or two inhibiting groups (3beta-sulfamate and 17alpha- or 20(S)-t-butylbenzyl or benzyl) were synthesized and tested for inhibition of steroid sulfatase activity. When only a sulfamate group was added to dehydroepiandrosterone, androst-5-ene-3beta,17beta-diol, pregnenolone and 20-hydroxy-pregnenolone, no significant inhibition of steroid sulfatase occurred at concentrations of 0.3 and 3 microM. With only a t-butylbenzyl or a benzyl group, a stronger steroid sulfatase inhibition was obtained in the androst-5-ene than in the pregn-5-ene series. Comparative results from the screening tests and the IC50 values have shown that the effect of a sulfamate moiety as a second inhibiting group can be combined to the t-butylbenzyl or benzyl effect in the C19 and C21 steroid series. The 3beta-sulfamoyloxy-17alpha-t-butylbenzyl-5-androsten-17beta-ol (10) was thus found to be the most active compound with IC50 values of 46 +/- 8 and 14 +/- 1 nM, respectively for the transformations of E1S to E1 and DHEAS to DHEA. The IC50 values of compound 10 are similar to that of 17alpha-t-butylbenzyl-estradiol, which was previously reported by our group as a good steroid sulfatase reversible inhibitor, but remains higher than that of the potent inactivators estrone-3-O-sulfamate (EMATE) and 17alpha-t-butylbenzyl-EMATE. However, contrary to these two latter inhibitors, compound 10 did not induce any proliferative effect on estrogen-sensitive ZR-75-1 cells nor on androgen-sensitive Shionogi cells at concentrations tested, suggesting that this steroid sulfatase inhibitor is non estrogenic and non androgenic.
Ciobanu
Liviu C
LC
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Quebec (CHUQ-Pavillon CHUL) 2705 Boulevard Laurier and Laval University, Québec, Qc., G1V 4G2, Canada.
Boivin
Roch P
RP
Luu-The
Van
V
Poirier
Donald
D
D000728:Androgens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004967:Estrogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013057:Spectrum Analysis / Q000379:methods; D043266:Steryl-Sulfatase; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000728:Androgens; D004791:Enzyme Inhibitors; D004967:Estrogens; D013451:Sulfonic Acids; C005741:sulfamic acid; D001192:Arylsulfatases; D043266:Steryl-Sulfatase