Protective effects of 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates on vascular cognitive impairment

Navdeep Kaur; Yao-Ching Fang; Hsueh-Yun Lee; Arshdeep Singh; Kunal Nepali; Mei-Hsiang Lin; Teng-Kuang Yeh; Mei-Jung Lai; Lung Chan; Yong-Kwang Tu; Suddhasatwa Banerjee; Chaur-Jong Hu; Jing-Ping Liou

doi:10.1016/j.ejmech.2019.111915

Protective effects of 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates on vascular cognitive impairment

Eur J Med Chem. 2020 Feb 1:187:111915. doi: 10.1016/j.ejmech.2019.111915. Epub 2019 Nov 26.

Authors

Affiliations

¹ School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
² Taipei Neuroscience Institute, Taipei Medical University, Taiwan.
³ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institute, Zhunan Town, Miaoli County, Taiwan.
⁴ TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan.
⁵ Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁶ Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taiwan.
⁷ Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taiwan. Electronic address: chaurjongh@tmu.edu.tw.
⁸ School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan. Electronic address: jpl@tmu.edu.tw.

PMID: 31838329
DOI: 10.1016/j.ejmech.2019.111915

Abstract

A series of 10,11-dihydro-5H-dibenzo [b,f]azepine hydroxamates (4-15) were synthesized, behaving as histone deacetylase inhibitors, and examined for their influence on vascular cognitive impairment (VCI), which correlated with dementia. The results revealed that (E)-3-(4-(((3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)propyl)amino)methyl)phenyl)-N-hydroxy-acrylamide (13) increases cerebral blood flow (CBF), attenuates cognitive impairment, and improves hippocampal atrophy in in vivo study. It is also able to increase the level of histone acetylation (H3K14 or H4K5) in the cortex and hippocampus of chronic cerebral hypoperfusion (CCH) mice; as a result, it could be a potential HDAC inhibitor for the treatment of vascular cognitive impairment.

Keywords: Histone deacetylase inhibitors; Neurodegenerative disease; Vascular cognitive impairment.

MeSH terms

Animals
Azepines / chemistry
Azepines / pharmacology*
Cell Line, Tumor
Clomipramine / analogs & derivatives*
Clomipramine / chemistry
Clomipramine / pharmacology
Cognitive Dysfunction / drug therapy*
Cognitive Dysfunction / metabolism
Dementia, Vascular / drug therapy*
Dementia, Vascular / metabolism
Dose-Response Relationship, Drug
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Protective Agents / chemical synthesis
Protective Agents / chemistry
Protective Agents / pharmacology*
Structure-Activity Relationship

Substances

10,11-dihydro-5H-dibenzo(b,f)azepine
Azepines
Histone Deacetylase Inhibitors
Hydroxamic Acids
Protective Agents
Histone Deacetylases
Clomipramine