Sulfonamides as Aromatase Inhibitors: Nimesulide Analogues, N-cyclic- and Aryl-Sulfonamides

Aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogens. Inhibitors of this key enzyme are used to treat hormone receptor-positive early, locally advanced, and metastatic breast cancers and are classified by structure into steroidal and nonsteroidal classes. Non-steroidal inhibitors, in particular, bind non-covalently to the heme moiety of aromatase and prevent the binding of the substrate androstenedione by saturating the binding site. Several aromatase inhibitors have been developed to date, most of which share a common pharmacophore: (i) one or two aromatic rings that contribute to hydrophobic interactions, (ii) a triazole or imidazole that coordinates with the heme iron of aromatase, and (iii) hydrophobic groups that help the molecule fit into the lipophilic binding pocket of aromatase. In recent years, several studies have focused on developing aromatase inhibitors containing a sulfonamide group, which can form significant interactions with aromatase due to its ability to participate in hydrogen bonding. This review aims to describe the most significant structure-activity relationships of nonsteroidal aromatase inhibitors containing a sulfonamide moiety, focusing on (i) biological results related to enzyme inhibition and (ii) interactions with active-site residues of aromatase identified through molecular modeling. Based on their core scaffold, the molecules are classified into (i) analogues of nimesulide, (ii) N-cyclic sulfonamides, and (iii) aryl-sulfonamides.