salicylates and 3-phenylsalicylic-acid

The first design, synthesis, and evaluation of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) inhibitors based on the recently published crystal structure of its ternary complex with inhibitor are reported. While the enzyme-inhibitor interactions observed in the crystal structure remain conserved with the newly designed inhibitors, the additional phenyl group of the most potent compound, 3-bromo-5-phenylsalicylic acid, targets a nonconserved hydrophobic pocket in the active site of AKR1C1 resulting in 21-fold improved potency (K(i) = 4 nM) over the structurally similar 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C2). The compound is hydrogen bonded to Tyr55, His117, and His222, and the phenyl ring forms additional van der Waals interactions with residues Leu308, Phe311, and the nonconserved Leu54 (Val in AKR1C2). Additionally, the metabolism of progesterone in AKR1C1-overexpressed cells was potently inhibited by 3-bromo-5-phenylsalicylic acid, which was effective from 10 nM with an IC(50) value equal to 460 nM.

Topics: 20-Hydroxysteroid Dehydrogenases; Catalytic Domain; Cell Line; Drug Design; Enzyme Inhibitors; Humans; Hydrogen Bonding; Progesterone; Protein Binding; Salicylates; Salicylic Acid; Structure-Activity Relationship

In the title compound, C13H10O3, there is a single type of intermolecular hydrogen bond. From this is formed a cyclic dimer about a twofold axis. In addition, there is an intramolecular hydrogen bond which is virtually identical to that observed in salicylic acid.

Topics: Crystallography, X-Ray; Hydrogen Bonding; Salicylates