11-amino-5-N-methyl-7-fluorine- quindoline derivatives: The Potential Anti-angiogenic Agents Targeting G-quadruplex Structure in Vascular Endothelial Cell Growth Factor

Tian-Miao Ou,Lian-Quan Gu,Xiao-Dong Wang,Zhi-Shu Huang,Yu-Jing Lu,Yan-Ping Li,Zeng-Yun An

doi:10.1038/npre.2008.1946.1

Abstract

AbstractVascular endothelial growth factor (VEGF), a pluripotent cytokine and angiogenic growth factor, plays crucial roles in embryonic development and tumour progression, and is over-expressed in many types of cancer and generally associated with tumour progression and survival rate. The polypurine/polypyrimide sequence located upstream (-89 to -43) of the promoter region of the human VEGF gene that can form specific G-quadruplex structures and raise the possibility for transcriptional control of the VEGF gene by G-quadruplex ligands. In the present study, we investigated the interaction between the 5-N-methyl-7-fluorine-quindoline derivatives (11-amino-5-N-methyl-7-fluorine- quindoline derivatives) and the G-rich sequence in VEGF&apos;s promoter and the subsequent effects on the biological functions of VEGF. We found the strong interaction between the 5-N-methyl-7-fluorine-quindoline derivatives and the G-rich DNA of VEGF, and this interaction might significantly influence the biological functions of VEGF, including the transcription and expression of VEGF, cell proliferation and apoptosis, and the stimulation of angiogenesis in chick embryo.

Highlights

Vascular endothelial growth factor (VEGF), a pluripotent cytokine and angiogenic growth factor, plays crucial roles in embryonic development, which acts as a potent inducer of vascular permeability, a survival and mitogen factor for endothelial cells in adults
We investigated the interaction between the 5-N-methyl-7-fluorine-quindoline derivatives and the G-rich sequence in VEGF’s promoter and the subsequent effects on the biological functions of VEGF
We found that strong interaction between the 5-N-methyl-7-fluorine-quindoline derivatives and the G-rich DNA of VEGF, and this interaction might significantly influence the biological functions of VEGF, including the transcription and expression of VEGF, cell proliferation and apoptosis, and the stimulation of angiogenesis in chick embryo

Summary

Introduction

Vascular endothelial growth factor (VEGF), a pluripotent cytokine and angiogenic growth factor, plays crucial roles in embryonic development, which acts as a potent inducer of vascular permeability, a survival and mitogen factor for endothelial cells in adults. The polypurine/polypyrimide sequence located upstream (-89 to -43) of the promoter region of the human VEGF gene, which serves as a multiple binding site for transcription factors, such as Sp1 and Egr-1, consists of five runs of at least three contiguous guanines. This tract can form specific G-quadruplex structures and raise the possibility for transcriptional control of the VEGF by G-quadruplex ligands (Sun et al, 2005). Since the expression of human VEGF is mainly regulated at the transcriptional level (Bikfalvi and Bicknell, 2002; Martiny-Baron and Marme, 1995), designing drugs targeting VEGF via stabilizing G-quadruplex in its promoter region seems to be a potent strategy

Methods

Results

Conclusion