Design and Synthesis of Vandetanib Derivatives Containing Nitroimidazole Groups as Tyrosine Kinase Inhibitors in Normoxia and Hypoxia.

Huiqiang Wei,Yiliang Li,Saijun Fan,Xiangbo Yang,Haihua Shang,Deguan Li,Dan Song

doi:10.3390/molecules21121693

Abstract

Sixteen novel epidermal growth factor receptor (EGFR)/vascular endothelial growth factor (VEGF)-2 inhibitors (nitroimidazole-substituted 4-anilinoquinazoline derivatives (16a–p)) were designed and prepared via the introduction of a nitroimidazole group in the piperidine side chain and modification on the aniline moiety of vandetanib. Preliminary biological tests showed that comparing with vandetanib, some target compounds exhibited excellent EGFR inhibitory activities and anti-proliferative over A549/H446 cells in hypoxia. Meanwhile, several of the above compounds demonstrated better bioactivity than vandetanib in VEGF gene expression inhibition. Owing to the excellent IC50 value (1.64 μmol/L), the inhibition ratios of 16f over A549 and H446 cells were 62.01% and 59.86% at the concentration of 0.5 μM in hypoxia, respectively. All of these results indicated that 16f was a potential cancer therapeutic agent in hypoxia and was worthy of further development.

Highlights

Hypoxia is a common phenomenon in most solid tumors [1,2]
Traditional radiotherapy and chemotherapy are invalid towards hypoxic tumor cells
The synthetic route displayed in Scheme 1 was started from 4-piperidine methanol (2) and nitroimidazoles

Summary

Introduction

Hypoxia is a common phenomenon in most solid tumors [1,2]. Hypoxic tumor cells are distant from blood vessels and general drugs are difficult to enter internal hypoxic tissues [2]. (HIF-1) can be promoted by hypoxia and enhance gene expression levels of some cell growth factors [4,5,6] and tyrosine kinase receptors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor-β (PDGF-β), and epidermal growth factor receptor (EGFR) [7]. These cell growth factors and tyrosine kinase receptors induce a series of cellular circumstances, such as angiogenesis, tumor cells proliferation and migration, through tyrosine kinase signaling pathways [5]. Overcoming hypoxic resistance of solid tumors has become a tremendous challenge in cancer therapy [8]

Methods

Results

Conclusion