2. Academic Validation
  3. 4-Indolyl-N-hydroxyphenylacrylamides as potent HDAC class I and IIB inhibitors in vitro and in vivo

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.
Samir Mehndiratta 1,  Ruei-Shian Wang 2,  Han-Li Huang 3,  Chih-Jou Su 3,  Chia-Ming Hsu 3,  Yi-Wen Wu 3,  Shiow-Lin Pan 4,  Jing-Ping Liou 5
Affiliations

Affiliations

  • 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: jpl@tmu.edu.tw.
PMID: 28395150 DOI: 10.1016/j.ejmech.2017.03.079
Abstract

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.

Keywords

Acrylamide; Cancer; HDAC; Hydroxamic acid; Indole; Prostate cancer.

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