Synthesis and evaluation of a photoresponsive quencher for fluorescent hybridization probes

Org Biomol Chem. 2014 Oct 21;12(39):7844-58. doi: 10.1039/c4ob01185f. Epub 2014 Sep 1.

Abstract

Nowadays, most nucleic acid detections using fluorescent probes rely on quenching of fluorescence by energy transfer from one fluorophore to another or to a non-fluorescent molecule (quencher). The most widely used quencher in fluorescent probes is 4-((4-(dimethylamino)phenyl)azo)benzoic acid (DABCYL). We targeted a nucleoside-DABCYL analogue which could be incorporated anywhere in an oligonucleotide sequence and in any number, and used as a quencher in different hybridization sensitive probes. Specifically, we introduced a 5-(4-((dimethylamino)phenyl)azo)benzene)-2'-deoxy-uridine (dU(DAB)) quencher. The photoisomerization and dU(DAB)'s ability to quench fluorescein emission have been investigated. We incorporated dU(DAB) into a series of oligonucleotide (ON) probes including strand displacement probes, labeled with both fluorescein (FAM) and dU(DAB), and TaqMan probes bearing one or two dU(DAB) and a FAM fluorophore. We used these probes for the detection of a DNA target in real-time PCR (RT-PCR). All probes showed amplification of targeted DNA. A dU(DAB) modified TaqMan RT-PCR probe was more efficient as compared to a DABCYL bearing probe (93% vs. 87%, respectively). Furthermore, dU(DAB) had a stabilizing effect on the duplex, causing an increase in Tm up to 11 °C. In addition we showed the photoisomerisation of the azobenzene moiety of dU(DAB) and the dU(DAB) triply-labeled oligonucleotide upon irradiation. These findings suggest that dU(DAB) modified probes are promising probes for gene quantification in real-time PCR detection and as photoswitchable devices.

MeSH terms

  • Chemistry Techniques, Synthetic
  • Deoxyuridine / chemistry
  • Fluorescent Dyes / chemical synthesis*
  • Fluorescent Dyes / chemistry*
  • Isomerism
  • Nucleic Acid Hybridization
  • Oligonucleotides / chemistry
  • Organophosphorus Compounds / chemistry
  • Photochemical Processes*
  • p-Dimethylaminoazobenzene / analogs & derivatives*
  • p-Dimethylaminoazobenzene / chemical synthesis
  • p-Dimethylaminoazobenzene / chemistry

Substances

  • Fluorescent Dyes
  • Oligonucleotides
  • Organophosphorus Compounds
  • phosphoramidite
  • 4-(4-dimethylaminophenylazo)benzoic acid
  • p-Dimethylaminoazobenzene
  • Deoxyuridine