Chemical synthesis of 16 beta-propylaminoacyl derivatives of estradiol andtheir inhibitory potency on type 1 17 beta-hydroxy steroid dehydrogenase and binding affinity on steroid receptors

The 17 beta -hydroxysteroid dehydrogenases (17 beta -HSDs) are members of a family of enzymes that catalyze the interconversion of weakly active sexua l hormones (ketosteroids) and potent hormones (17 beta -hydroxysteroids). A mong the known isoforms of 17 beta -HSD, the type I catalyzes the NAD(P)H-m ediated reduction of estrone (E-1) to estradiol (E-2), a predominant mitoge n for the breast cancer cells. Therefore, the inhibition of this particular enzyme is a logical approach to reduce the concentration of estradiol in b reast tumors. To develop inhibitors of type 1 17 beta -HSD activity, we hyp othesized that molecules containing both hydrophobic and hydrophilic compon ents should be interesting candidates for interacting with both the steroid binding domain and some amino acid residues of the cofactor binding domain of the enzyme. Firstly, a conveniently protected 16 beta-(3-aminopropyl)-E -2 derivative was synthesized from commercially available E-1. Then, a repr esentative of all class of NHBoc-protected amino acids (basic, acid, aromat ic, aliphatic, hydroxylated) were coupled using standard procedures to the amino group of the precursor. Finally, cleavage of all protecting groups wa s performed in a single step to generate a series of 16 beta -propylaminoac yl derivatives of E-2. The enzymatic screenings revealed that none of the n ovel compounds can inhibit the reductive activity of type 1 17 beta -HSD. O n the other hand, all of these E-2 derivatives did not show any significant binding affinity on four steroid receptors including the estrogen receptor . Additional efforts aimed at improving the inhibitory potency of these ste roidal derivatives on type 1 17 beta -HSD without providing estrogenic acti vities is under investigation using a combinatorial chemistry approach. (C) 2001 Elsevier Science Inc. All rights reserved.