4-Indolyl-N-hydroxyphenylacrylamides as potent HDAC class I and IIB inhibitors in vitro and in vivo
- Eur J Med Chem. 2017 Jul 7:134:13-23. doi: 10.1016/j.ejmech.2017.03.079.
- 1. School of Pharmacy, College of Pharmacy, Taipei Medical University (TMU), Taiwan.
- 2. PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, TMU, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taiwan.
- 3. PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, TMU, Taiwan.
- 4. PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, TMU, Taiwan; Department of Pharmacology, College of Medicine, Taipei Medical University, Taiwan.
- 5. School of Pharmacy, College of Pharmacy, Taipei Medical University (TMU), Taiwan. Electronic address: [email protected].
A series of 4,5-indolyl-N-hydroxyphenylacrylamides, as HDAC inhibitors, has been synthesized and evaluated in vitro and in vivo. 4-Indolyl compounds 13 and 17 functions as potent inhibitors of HDAC1 (IC50 1.28 nM and 1.34 nM) and HDAC 2 (IC50 0.90 and 0.53 nM). N-Hydroxy-3-{4-[2-(1H-indol-4-yl)-ethylsulfamoyl]-phenyl}-acrylamide (13) inhibited the human Cancer cell growth of PC3, A549, MDA-MB-231 and AsPC-1 with a GI50 of 0.14, 0.25, 0.32, and 0.24 μM, respectively. In in vivo evaluations bearing prostate PC3 xenografts nude mice model, compound 13 suppressed tumor growth with a tumor growth inhibition (TGI) of 62.2%. Immunohistochemistry of protein expressions, in PC-3 xenograft model indicated elevated acetyl-histone 3 and prominently inhibited HDAC2 protein expressions. Therefore, compound 13 could be a suitable lead for further investigation and the development of selective HDAC 2 inhibitors as potent anti-cancer compounds.