Synthesis and importance of bulky aromatic cap of novel SAHA analogs for HDAC inhibition and anticancer activity

On the basis of potent HDAC-inhibitory activity and anticancer activity of SAHA, novel SAHA derivatives 3a-d and 7 with a bulky cap such as p-dimethylaminophenyl, 4-phenylaminophenyl, 4-phenyloxyphenyl, 9Hfluorenyl or naphthalenyl ring were synthesized starting from the corresponding aryl amines or naphthalenyl acetic acid using an EDC-mediated amide coupling reaction in the presence of HOBt followed by a nucleophilic addition-elimination reaction with hydroxylamine. Compounds 3b, 3c and 3d showed more potent inhibitory activity on total HDACs (14∼27-fold), HDAC1 (8∼15-fold), HDAC2 (1.3∼25-fold) and HDAC7 (1∼3-fold) and more potent anticancer activity (2∼22-fold) against MCF-7, MDA-MB-231, MCF-7/ Dox, MCF-7/Tam, SK-OV-3, LNCaP and PC3 human cancer cell lines than SAHA.