Synthesis and evaluation of estradiol derivatives with 16α-(bromoalkylamide), 16α-(bromoalkyl) or 16α-(bromoalkynyl) side chain as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 without estrogenic activity Original Research Article

To develop inhibitors of 17β-hydroxysteroid dehydrogenase (17β-HSD) without residual estrogenic activity, the synthesis of 16α-(bromoalkylamide) derivatives of estradiol was performed starting from a key intermediate aldehyde obtained from commercially available estrone. In addition, series of 16α-(bromoalkyl) and 16α-(bromoalkynyl) derivatives of estradiol were also prepared as model compounds. All new compounds inhibited human placental cytosolic 17β-HSD (type 1) with IC50 values ranging from 1.7 to 10.6 μM. From these results, we observed that a primary bromide produces a greater inhibition of 17β-HSD activity than secondary bromide, and that a shorter 16α-side chain increases the inhibiting activity. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, the 16α-(bromoalkylamide)-estradiol series had no estrogenic activity at 30 nM, and only the compound with a shorter side chain length showed an estrogenic activity at 1000 nM. Interestingly, at this concentration, the compound with an intermediate side chain length showed an antiestrogenic activity of 74%, whereas the compound with the longer side chain length showed 34% of antiestrogenic activity. In this test, other 17β-HSD inhibitors (without bromoalkylamide side chain) were fully estrogenic. Among synthesized compounds, the estradiol derivative 4 (N-butyl, N-methyl, 9-[3′,17′β-(dihydroxy)-1′,3′,5′(10′)-estratrien-16′α-yl]-7-bromononamide) was the best compromise for a dual-action inhibitor. This compound inhibited moderately and reversibly the 17β-HSD type 1 activity, but possessed no estrogenic activity and exhibited antiestrogenic activity in the ZR-75-1 cell line.