Directed C–H activation of 13α-estrone: a pathway to promising AKR1C inhibitors <i>via</i> docking and biological studies

The aldo-keto reductase isoenzymes AKR1C1-3 regulate local steroid hormone availability through the interconversion of active and inactive ligands, thereby modulating prereceptor signaling. This regulatory mechanism has been implicated in the progression of hormone-dependent malignancies, highlighting AKR1C enzymes as attractive therapeutic targets for endocrine-related cancers. The AKR1C family is also known to mediate resistance to multiple classes of chemotherapeutic agents through various mechanisms. Inhibition of AKR1C enzymes may therefore potentiate the cytotoxic effects of chemotherapeutic agents. Building on our recent work describing potent A-ring halogenated 13α-estrone-based AKR1C inhibitors, we now report further structural modifications <i>via</i> directed C-H activation on the same scaffold. Following the introduction of a directing group, hydroxylation or acetoxylation was performed at the C-2 position. The newly synthesized compounds were evaluated against recombinant AKR1C1-3 enzymes. Notably, two new derivatives (4 and 6a) exhibited low micromolar, isoform-selective inhibitory activity against AKR1C2. Moreover, using <i>in silico</i> molecular docking, we postulated the binding conformations of active pyridyloxy derivative (6a), triazinyl derivative (7) and aryl carbamate (4) within the AKR1C2 binding site, with all of them showing key interactions with Trp86, Val128, Ile129 and Trp227. The AKR1C2 inhibitors identified in this study represent promising starting points for the development of novel therapeutic agents, limiting metastatic dissemination, particularly in certain aggressive tumor types. Given that AKR1C1-3 isoenzymes often catalyze overlapping biochemical transformations, inhibition of one member may be compensated by another. Thus, while selective AKR1C inhibitors remain valuable, the development of pan-inhibitors also represents a promising therapeutic strategy.