LAUSR

A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β‐carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low‐micromolar range. In particular, the HDAC inhibition IC50 value of N‐(2‐(dimethylamino)ethyl)‐N‐(4‐(hydroxylcarbamoyl)benzyl)‐1‐(4‐methoxyphenyl)‐9H‐pyrido[3,4‐b]indole‐3‐carboxamide (9 h) is five‐fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat). Furthermore, 9 h was found to increase the acetylation of histone H3 and α‐tubulin, and to induce DNA damage as evidenced by hypochromism and enhanced phosphorylation of histone H2AX. Compound 9 h inhibits Stat3, Akt, and ERK signaling, important cell‐growth‐promoting pathways that are aberrantly activated in most cancers. Finally, 9 h showed reasonable solubility and permeability in Caco‐2 cells. Our findings suggest that these novel β‐carboline‐based HDAC inhibitors may hold great promise as therapeutic agents for the treatment of human cancers.