Design, synthesis and biological evaluation of Exemestane derivatives as potent inhibitors of Aromatase

Aromatase is a member of the cytochrome P450 superfamily, responsible for a key step in the biosynthesis of estrogens, allowing the aromatization of androgens into estrogens. For this reason, it is a very valuable therapeutic target for the selective treatment of estrogen-dependent breast cancer. Among aromatase inhibitors (AIs), Exemestane is an irreversible, steroidal aromatase inactivator of type I of clinical use. X-Ray studies revealed the existence of an access channel cavity (ACC) in correspondence of the C-4 and C-6 positions of the androstenedione complexed with aromatase [1]. This led to the design of C-6 alkyl-substituted steroids in order to better anchor in the described ACC, resulting in very efficient inhibition [2]. Starting from this evidence, we have designed, synthesized and biologically tested new series of steroidal androstanes having additional C-6 or C-7 methyl, allyl or hydroxyl groups. Among them, compound 13 (Figure 1) showed a potency and affinity to aromatase similar to Exemestane. Molecular modelling studies guided by the GRID MIFs, were useful to rationalize the best inhibition potency of 13 [3].