Identification of a new G-quadruplex motif in the KRAS promoter and design of pyrene-modified G4-decoys with antiproliferative activity in pancreatic cancer cells

Susanna Cogoi; Manikandan Paramasivam; Vyacheslav Filichev; Imrich Géci; Erik B Pedersen; Luigi E Xodo

doi:10.1021/jm800874t

Identification of a new G-quadruplex motif in the KRAS promoter and design of pyrene-modified G4-decoys with antiproliferative activity in pancreatic cancer cells

J Med Chem. 2009 Jan 22;52(2):564-8. doi: 10.1021/jm800874t.

Authors

Susanna Cogoi¹, Manikandan Paramasivam, Vyacheslav Filichev, Imrich Géci, Erik B Pedersen, Luigi E Xodo

Affiliation

¹ Department of Biomedical Science and Technology, School of Medicine, P.le Kolbe 4, 33100 Udine, Italy.

PMID: 19099510
DOI: 10.1021/jm800874t

Abstract

A new quadruplex motif located in the promoter of the human KRAS gene, within a nuclease hypersensitive element (NHE), has been characterized. Oligonucleotides mimicking this quadruplex are found to compete with a DNA-protein complex between NHE and a nuclear extract from pancreatic cancer cells. When modified with (R)-1-O-[4-1-(1-pyrenylethynyl) phenylmethyl]glycerol insertions (TINA), the quadruplex oligonucleotides showed a dramatic increase of the T(m) (deltaT(m) from 22 to 32 degrees C) and a strong antiproliferative effects in Panc-1 cells.

Publication types

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

MeSH terms

Base Sequence
Cell Line, Tumor
Cell Proliferation / drug effects*
Electrophoretic Mobility Shift Assay
G-Quadruplexes*
Genes, ras*
Glycerol / analogs & derivatives
Glycerol / chemistry
Humans
Pancreatic Neoplasms / pathology*
Promoter Regions, Genetic*
Pyrenes / chemistry
Pyrenes / pharmacology*

Substances

(R)-1-O-(4-(1-pyrenylethynyl)phenylmethyl)glycerol
Pyrenes
pyrene
Glycerol