Open AccessChemical Synthesis and NMR Characterization of Non Steroidal Mimics of an Estradiol Derivative Used as Inhibitor of 17beta-Hydroxysteroid Dehydrogenase Type 1
Author(s) -
Guy Bertrand Djigoué,
René Maltais,
Charles Ouellet,
Alexandre Trottier,
Donald Poirier
Publication year - 2012
Publication title -
international journal of chemistry
Language(s) - English
Resource type - Journals
eISSN - 1916-9701
pISSN - 1916-9698
DOI - 10.5539/ijc.v4n6p75
Subject(s) - chemistry , stereochemistry , dehydrogenase , hydrobromide , amino acid , enzyme , hydrolysis , in vitro , nucleophilic substitution , nucleophile , protecting group , combinatorial chemistry , catalysis , biochemistry , alkyl , organic chemistry
Inhibiting estradiol (E2) biosynthesis through 17?-hydroxysteroid dehydrogenase type 1 (17?-HSD1) inhibitors is a promising strategy for breast cancer therapy. We have designed a non-steroidal template to mimic CC-156, a potent steroidal inhibitor of 17?-HSD1. Starting from tetrahydro-isoquinolinol hydrobromide, two representative compounds were synthesized in six chemical steps: protection of the amino group, protection of the phenol, hydrolysis of the N-protecting group Fmoc, nucleophilic substitution to introduce an ethyloxirane, phenolysis with meta or para hydroxybenzamide and the hydrolysis of the MOM protecting group. Although the compounds showed a good fit when docked in the catalytic site of the enzyme, conserving the key interactions with amino acids His221 and Ser142, observed from the crystalline structure of inhibitor CC-156 with 17?-HSD1, they weakly inhibited 17?-HSD1. However, they did not show estrogenic activity when tested in vitro, suggesting the potential of this non-steroidal template for drug design. Furthermore, the synthetic approach reported here opens a door to the preparation of additional non-steroidal mimics of E2 derivatives, which could be tested on 17?-HSD1 and others biological targets