Effect of phenylurea hydroxamic acids on histone deacetylase and VEGFR-2

Szu Lee; Shih-Wei Wang; Chen-Lin Yu; Huai-Ching Tai; Juei-Yu Yen; Yu-Lien Tuan; Hsueh-Hsiao Wang; Yi-Ting Liu; Shiou-Sheng Chen; Hsueh-Yun Lee

doi:10.1016/j.bmc.2021.116454

Effect of phenylurea hydroxamic acids on histone deacetylase and VEGFR-2

Bioorg Med Chem. 2021 Nov 15:50:116454. doi: 10.1016/j.bmc.2021.116454. Epub 2021 Oct 4.

Authors

Affiliations

¹ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
² Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
⁴ School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan.
⁵ Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
⁶ Division of Urology, Taipei City Hospital Zhong Xiao Branch, Taipei, Taiwan; Commission for General Education, National Taiwan University of Science and Technology, Taipei, Taiwan; Department of Urology, College of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; General Education Center, University of Taipei, Taipei, Taiwan. Electronic address: dab67@tpech.gov.tw.
⁷ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan; Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: hyl@tmu.edu.tw.

PMID: 34634618
DOI: 10.1016/j.bmc.2021.116454

Abstract

A series of phenylurea hydroxamic acids incorporating pharmacophores of inhibitors of HDAC inhibitors and VEGFR-2 has been designed. Most of the compounds show antiproliferative activity comparable to that of Vorinostat and Sorafenib, and better EPC inhibitory activity. Enzymatic assays and Western blotting results indicated that compound 14 not only inhibits HDAC but also has slight VEGFR-2 inhibitory activity. A docking study revealed that the polar hydroxamic acid retains the interaction with HDAC through a zinc ion and also interacts with some residues of the active site of VEGFR-2. Despite 14 displaying a weaker VEGFR-2 activity, a possible route to develop potent HDAC/VEGFR-2 inhibitors is suggested.

Keywords: HDAC; Phenylurea; VEGFR-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
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*
Molecular Structure
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Hydroxamic Acids
Phenylurea Compounds
Protein Kinase Inhibitors
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2
Histone Deacetylases