Testosterone Based Esters as Inhibitors of Aromatase (AR) and the use of the Substrate-Haem Complex Approach in the Rationalisation of the Inhibitory Activity of these Compounds

The synthesis, biochemical evaluation and molecular modelling of a series of esters based upon testosterone is described. The compounds were tested for human placental aromatase (AR) inhibition in vitro and were found, in general, to be weaker than the standard non-steroidal compound, aminoglutethimide (AG), however, one compound [testosterone 4-nitrobenzoate (15)] was found be some six times more potent than AG. The inhibitory activity of the compounds was rationalised through the use of the novel substrate-haem complex (SHC) approach and suggests that the longer alkyl chain containing compounds bind in a manner that results in steric hindrance between the active site of AR and the carboxylate moiety of the compounds, as such, reduced inhibitory activity is observed. The modelling of compound 15 suggests that an additional hydrogen-bonding group may be present at the active site, which allows this compound to possess greatly increased potency. Keywords: hydrogen-bonding, carboxylate moiety, testosterone 4-nitrobenzoate, Aromatase