Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms

Autor: Mei Chuan Chen, Samir Mehndiratta, Hsueh Yun Lee, Jing Ping Liou, Yuh Hsuan Chao, Mei Jung Lai, Cheng Hsin Lee
Jazyk: angličtina
Rok vydání: 2020
Předmět:
hydroxamic acid
Population
Quinoline
Caspase 3
Antineoplastic Agents
RM1-950
Histone Deacetylase 6
Hydroxamic Acids
01 natural sciences
chemistry.chemical_compound
Structure-Activity Relationship
Western blot
HDAC
Drug Discovery
medicine
Tumor Cells
Cultured
Humans
Fragmentation (cell biology)
education
Cell Proliferation
Pharmacology
education.field_of_study
Hydroxamic acid
medicine.diagnostic_test
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Chemistry
General Medicine
Molecular biology
0104 chemical sciences
Histone Deacetylase Inhibitors
Isoenzymes
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
lung cancer
colon cancer
Cell culture
Apoptosis
acrylamide
Quinolines
Therapeutics. Pharmacology
Histone deacetylase
Drug Screening Assays
Antitumor
Research Article
Research Paper
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry
article-version (VoR) Version of Record
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 74-84 (2021)
ISSN: 1475-6374
1475-6366
Popis: A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.
Graphical Abstract
Databáze: OpenAIRE
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