Design, synthesis, and biological evaluation of novel amide and hydrazide based thioether analogs targeting Histone deacteylase (HDAC) enzymes

Ayman B. Farag, Heba A. Ewida, Mahmoud Salama Ahmed

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Development of HDAC inhibitors have become an ultimate need targeting different types of cancer. In silico virtual screening was applied to screen novel scaffolds via scaffold hopping strategy to develop different acrylamide and aryl/heteroaryl hydrazide based analogs merged with thioether moiety. The acrylamide based analogs showed significant hydrophobic interaction within binding pocket in addition to co-ordination with Zn+2 via carbonyl group, however the aryl/heteroaryl hydrazide based analogs showed binding towards Zn+2 via thiol moiety. Two classes (acrylamide and aryl/heteroaryl hydrazide based analogs) were synthesized to be screened along with 60 cancer cell lines panel to reveal that both of AHM-4 and AHM-5 showed significant inhibitory growth against HL-60 (Leukemia cell lines) at GI50 2.87 μM and 3.20 μM, respectively and MDA-MB-435 (Melanoma cell lines) cell lines at GI50 of 0.37 μM and 0.42 μM, respectively. AHM-4 and AHM-5 showed general inhibitory profile against class I HDAC enzymes with differential inhibitory activity towards HDAC 2 at IC50 32 nM and 20 nM, respectively via ELISA enzymatic assay, in addition to inhibiting activity for the expression of class I HDAC enzymes via real time PCR with differential selective inhibition against HDAC 2 up to 10 folds, compared to control. AHM4 and AHM5 showed cell cycle arrest action at G2/M phase along with induction of apoptosis via assessment of apoptotic parameters such as Caspase 3, 9, and γ- H2AX. The synthesized analogs offer novel scaffold to be further optimized for development of HDAC inhibitors.

Original languageEnglish (US)
Pages (from-to)73-85
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume148
DOIs
StatePublished - Mar 25 2018
Externally publishedYes

Fingerprint

Sulfides
Amides
Histones
Cells
Acrylamide
Enzymes
Scaffolds
Cell Line
Caspase 9
G2 Phase
HL-60 Cells
Enzyme Assays
Cell Cycle Checkpoints
Hydrophobic and Hydrophilic Interactions
Sulfhydryl Compounds
Caspase 3
Cell Division
Computer Simulation
Inhibitory Concentration 50
Real-Time Polymerase Chain Reaction

Keywords

  • Acrylamide
  • HDAC
  • Hydrazide
  • Scaffold hopping
  • Thioether

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "Design, synthesis, and biological evaluation of novel amide and hydrazide based thioether analogs targeting Histone deacteylase (HDAC) enzymes",
abstract = "Development of HDAC inhibitors have become an ultimate need targeting different types of cancer. In silico virtual screening was applied to screen novel scaffolds via scaffold hopping strategy to develop different acrylamide and aryl/heteroaryl hydrazide based analogs merged with thioether moiety. The acrylamide based analogs showed significant hydrophobic interaction within binding pocket in addition to co-ordination with Zn+2 via carbonyl group, however the aryl/heteroaryl hydrazide based analogs showed binding towards Zn+2 via thiol moiety. Two classes (acrylamide and aryl/heteroaryl hydrazide based analogs) were synthesized to be screened along with 60 cancer cell lines panel to reveal that both of AHM-4 and AHM-5 showed significant inhibitory growth against HL-60 (Leukemia cell lines) at GI50 2.87 μM and 3.20 μM, respectively and MDA-MB-435 (Melanoma cell lines) cell lines at GI50 of 0.37 μM and 0.42 μM, respectively. AHM-4 and AHM-5 showed general inhibitory profile against class I HDAC enzymes with differential inhibitory activity towards HDAC 2 at IC50 32 nM and 20 nM, respectively via ELISA enzymatic assay, in addition to inhibiting activity for the expression of class I HDAC enzymes via real time PCR with differential selective inhibition against HDAC 2 up to 10 folds, compared to control. AHM4 and AHM5 showed cell cycle arrest action at G2/M phase along with induction of apoptosis via assessment of apoptotic parameters such as Caspase 3, 9, and γ- H2AX. The synthesized analogs offer novel scaffold to be further optimized for development of HDAC inhibitors.",
keywords = "Acrylamide, HDAC, Hydrazide, Scaffold hopping, Thioether",
author = "Farag, {Ayman B.} and Ewida, {Heba A.} and Ahmed, {Mahmoud Salama}",
year = "2018",
month = "3",
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T1 - Design, synthesis, and biological evaluation of novel amide and hydrazide based thioether analogs targeting Histone deacteylase (HDAC) enzymes

AU - Farag, Ayman B.

AU - Ewida, Heba A.

AU - Ahmed, Mahmoud Salama

PY - 2018/3/25

Y1 - 2018/3/25

N2 - Development of HDAC inhibitors have become an ultimate need targeting different types of cancer. In silico virtual screening was applied to screen novel scaffolds via scaffold hopping strategy to develop different acrylamide and aryl/heteroaryl hydrazide based analogs merged with thioether moiety. The acrylamide based analogs showed significant hydrophobic interaction within binding pocket in addition to co-ordination with Zn+2 via carbonyl group, however the aryl/heteroaryl hydrazide based analogs showed binding towards Zn+2 via thiol moiety. Two classes (acrylamide and aryl/heteroaryl hydrazide based analogs) were synthesized to be screened along with 60 cancer cell lines panel to reveal that both of AHM-4 and AHM-5 showed significant inhibitory growth against HL-60 (Leukemia cell lines) at GI50 2.87 μM and 3.20 μM, respectively and MDA-MB-435 (Melanoma cell lines) cell lines at GI50 of 0.37 μM and 0.42 μM, respectively. AHM-4 and AHM-5 showed general inhibitory profile against class I HDAC enzymes with differential inhibitory activity towards HDAC 2 at IC50 32 nM and 20 nM, respectively via ELISA enzymatic assay, in addition to inhibiting activity for the expression of class I HDAC enzymes via real time PCR with differential selective inhibition against HDAC 2 up to 10 folds, compared to control. AHM4 and AHM5 showed cell cycle arrest action at G2/M phase along with induction of apoptosis via assessment of apoptotic parameters such as Caspase 3, 9, and γ- H2AX. The synthesized analogs offer novel scaffold to be further optimized for development of HDAC inhibitors.

AB - Development of HDAC inhibitors have become an ultimate need targeting different types of cancer. In silico virtual screening was applied to screen novel scaffolds via scaffold hopping strategy to develop different acrylamide and aryl/heteroaryl hydrazide based analogs merged with thioether moiety. The acrylamide based analogs showed significant hydrophobic interaction within binding pocket in addition to co-ordination with Zn+2 via carbonyl group, however the aryl/heteroaryl hydrazide based analogs showed binding towards Zn+2 via thiol moiety. Two classes (acrylamide and aryl/heteroaryl hydrazide based analogs) were synthesized to be screened along with 60 cancer cell lines panel to reveal that both of AHM-4 and AHM-5 showed significant inhibitory growth against HL-60 (Leukemia cell lines) at GI50 2.87 μM and 3.20 μM, respectively and MDA-MB-435 (Melanoma cell lines) cell lines at GI50 of 0.37 μM and 0.42 μM, respectively. AHM-4 and AHM-5 showed general inhibitory profile against class I HDAC enzymes with differential inhibitory activity towards HDAC 2 at IC50 32 nM and 20 nM, respectively via ELISA enzymatic assay, in addition to inhibiting activity for the expression of class I HDAC enzymes via real time PCR with differential selective inhibition against HDAC 2 up to 10 folds, compared to control. AHM4 and AHM5 showed cell cycle arrest action at G2/M phase along with induction of apoptosis via assessment of apoptotic parameters such as Caspase 3, 9, and γ- H2AX. The synthesized analogs offer novel scaffold to be further optimized for development of HDAC inhibitors.

KW - Acrylamide

KW - HDAC

KW - Hydrazide

KW - Scaffold hopping

KW - Thioether

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