Synthesis and Importance of Bulky Aromatic Cap of Novel SAHA Analogs for HDAC Inhibition and Anticancer Activity

• Published in: Bulletin of the Korean Chemical Society Vol. 32; no. 6; pp. 1891 - 1896
• Main Authors: Chun, Pu-Soon, Kim, Won-Hee, Kim, Jung-Su, Kang, Jin-Ah, Lee, Hye-Jin, Park, Ji-Young, Ahn, Mee-Young, Kim, Hyung-Sik, Moon, Hyung-Ryong
• Format: Journal Article
• Language: Korean
• Published: 2011
• Subjects: SAHA; HDAC inhibition; Anticancer activity; Bulky cap
• ISSN: 0253-2964

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, 9H-fluorenyl 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.