Its ester prodrug 20ac has limited solubility.

Its methyl ester prodrug 20b and the more lipophilic benzyl derivative 9ac, however, show significant reduction in cell proliferation. Effect of JMJD2A inhibitors on proliferation of KYSE-150 cells.Ĭompounds with high polarity such as 9b show no effect, presumably due to limited cell penetration. Full experimental details can be found in the Supplementary Information. (B) Synthesis route for N-morpholinoethyl ester 22ag of the most potent inhibitor. (A) Synthesis scheme for synthesis of compounds of the general lead structure 9 and their methyl ester prodrugs 20. Synthesis of analogs and prodrugs of lead structure 9. Water molecules are shown as red spheres, the ferrous ion as cyan sphere, H-bond and salt bridge interactions as yellow dashed lines and the metal coordination as gray dashed lines. Only the side chains of the protein residues involved in the interaction are shown. (B) Docking pose of 9a (orange) in JMJD2A (green, PDB code: 3pdq). The metal-coordinating atoms are colored in blue.

Ar stands for any N-containing aromatic ring. (A) Metal-binding motifs selected for filtering the ZINC drug-like database. Virtual screening campaign towards novel JmjC inhibitors. Chemical structure of the enzyme's cosubstrate 2-oxoglutarate 1a and summary of previously reported JumonjiC demethylase inhibitors (1b – 8).

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