Double-edged Swords: Diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis

Neha Upadhyay; Kalpana Tilekar; Sabreena Safuan; Alan P Kumar; Markus Schweipert; Franz-Josef Meyer-Almes; C S Ramaa

doi:10.1016/j.bioorg.2021.105350

Double-edged Swords: Diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis

Bioorg Chem. 2021 Nov:116:105350. doi: 10.1016/j.bioorg.2021.105350. Epub 2021 Sep 11.

Authors

Neha Upadhyay¹, Kalpana Tilekar¹, Sabreena Safuan², Alan P Kumar³, Markus Schweipert⁴, Franz-Josef Meyer-Almes⁵, C S Ramaa⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India.
² School of Health Sciences, Health Campus Universiti Sains 16150 Kubang Kerian, Kelantan, Malaysia.
³ Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁴ Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany.
⁵ Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany. Electronic address: [email protected].
⁶ Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India. Electronic address: [email protected].

PMID: 34547645
DOI: 10.1016/j.bioorg.2021.105350

Abstract

In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.

Keywords: Anti-tumor; HDAC; Multi-targeting; Synthesis; VEGFR-2.

Publication types

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

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / 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
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Neovascularization, Pathologic / drug therapy*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / metabolism
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis
Thiazolidinediones / chemistry
Thiazolidinediones / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Histone Deacetylase Inhibitors
Protein Kinase Inhibitors
Pyrazoles
Repressor Proteins
Thiazolidinediones
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2
HDAC4 protein, human
Histone Deacetylases