C6-(N,N-butyl-methyl-heptanamide) derivatives of estrone and estradiol as inhibitors of type 1 17β-hydroxysteroid dehydrogenase:: Chemical synthesis and biological evaluation

A series of estrone and estradiol derivatives having an N-butyl,methyl heptanamide side chain at C6-position were synthesized, tested as inhibitors of type 1 17 beta-HSD and assessed for their possible estrogenic activity. A better type I 17 beta-HSD inhibition was obtained for the 6 beta-side chain orientation over 6 alpha; the C17-alcohols are more potent inhibitors than the corresponding ketones; introducing a 2-methoxy group decreased the inhibitory potency; and the replacement of a C-S bond by a C-C bond in the C6 beta-side chain is not detrimental to inhibition. Interestingly, the new inhibitors were also found less estrogenic than the lead compound in two breast cancer cell lines, T-47D and MCF-7. (c) 2006 Elsevier Ltd. All rights reserved.