4-Indolyl-N-hydroxyphenylacrylamides as potent HDAC class I and IIB inhibitors in vitro and in vivo

Samir Mehndiratta; Ruei-Shian Wang; Han-Li Huang; Chih-Jou Su; Chia-Ming Hsu; Yi-Wen Wu; Shiow-Lin Pan; Jing-Ping Liou

doi:10.1016/j.ejmech.2017.03.079

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. Epub 2017 Mar 31.

Authors

Samir Mehndiratta¹, Ruei-Shian Wang², Han-Li Huang³, Chih-Jou Su³, Chia-Ming Hsu³, Yi-Wen Wu³, Shiow-Lin Pan⁴, Jing-Ping Liou⁵

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.

MeSH terms

Acrylamides / chemistry*
Acrylamides / pharmacology
Acrylamides / therapeutic use*
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Cell Proliferation / drug effects
Histone Deacetylase 1 / antagonists & inhibitors
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / antagonists & inhibitors
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use*
Humans
Indoles / chemistry
Indoles / pharmacology
Indoles / therapeutic use
Male
Mice
Mice, Nude
Neoplasms / drug therapy
Neoplasms / metabolism
Neoplasms / pathology
Prostate / drug effects
Prostate / metabolism
Prostate / pathology
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Xenograft Model Antitumor Assays

Substances

Acrylamides
Antineoplastic Agents
Histone Deacetylase Inhibitors
Indoles
Histone Deacetylase 1
Histone Deacetylase 2