Discovery of potent histone deacetylase inhibitors with modified phenanthridine caps

In discovery of novel HDAC inhibitory with anticancer potency, pharmacophores of phenanthridine were introduced to the structure of HDAC inhibitors. Fatty and aromatic linkers were evaluated for their solubility and activity. Both enzyme inhibitory and in vitro antiproliferative (against U937 cells) screening results revealed better activities of compounds with aromatic linker than molecules with fatty linker. Compared with SAHA (IC50 values of 1.34, 0.14, 2.58, 0.67 and 18.17 mu M), molecule Fb-4 exhibited 0.87, 0.09, 0.32, 0.34 and 17.37 mu M of IC50 values against K562, U266, MCF-7, U937 and HEPG2 cells, respectively. As revealed by cell cycle and apoptotic analysis, induction of G2/M phase arrest and apoptosis plays an important role in the inhibition of MCF-7 cells by Fb-4. Generally, a potent HDAC inhibitor was developed in the present study which could be utilised as a lead compound for further anticancer drug design.

Automated summary

In this study, pharmacophores of phenanthridine were incorporated into HDAC inhibitors, and fatty and aromatic linkers were evaluated for solubility and activity. Compounds with aromatic linker showed better activities than those with fatty linker. Molecule Fb-4 exhibited promising anticancer potency by inducing G2/M phase arrest and apoptosis in MCF-7 cells, suggesting its potential as a lead compound for further drug design.