2-(Phenylsulfonyl)quinoline N-hydroxyacrylamides as potent anticancer agents inhibiting histone deacetylase

• A series of 2-(phenylsulfonyl)quinoline N-hydroxyacrylamides were designed and synthesized.
• Two compounds (8f and 8j) with potent antiproliferative activity were identified.
• Compounds 8f was potent to inhibit HDAC function.

This study reports the design and synthesis of 2-(phenylsulfonyl)quinoline N-hydroxyacrylamides (8a–k). Structure-activity relationship studies focusing on regio-effect of N-hydroxyacrylamide moiety and influence of the sulfonyl linker revealed that N-hydroxy-3-[3-(quinoline-2-sulfonyl)-phenyl]-acrylamide (8f) showed remarkable enzymatic and cellular activity. The GI50 values of 8f for HL-60, HCT116, PC-3, and A549 cells were found to be 0.29, 0.08, 0.15, and 0.27 μM, respectively. The compounds are therefore more potent than FDA approved PXD-101 and SAHA. They also have an effect on the acetylation degree of histone H3 and α-tubulin. In in vivo studies, 8f showed marked inhibition of the growth of HCT116 xenografts.

The 2-(phenylsulfonyl)quinoline N-hydroxyacrylamide derivative 8f showed potent antiproliferative activity with anti-HDAC activity.Figure optionsDownload as PowerPoint slide