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

Upadhyay N 1 , Tilekar K 1 , Safuan S 2 , Kumar AP 3 , Schweipert M 4 , Meyer-Almes FJ 5 Show all authors , Ramaa CS 6

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: franz-josef.meyer-almes@h-da.de
  • 6 Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India. Electronic address: sinharamaa@yahoo.in
Bioorg Chem, 2021 11;116:105350.
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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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