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

<p> 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. </p><p> 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. </p><p> 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. </p><p> 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. </p>