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Guanidinium-modified phthalocyanines as high affinity G-quadruplex fluorescent probes and transcriptional regulators


Alzeer, J; Vummidi, B R; Roth, P J C; Luedtke, N W (2009). Guanidinium-modified phthalocyanines as high affinity G-quadruplex fluorescent probes and transcriptional regulators. Angewandte Chemie Internationale Edition, 48(49):9362-9365.

Abstract

In this manuscript we describe a guanidinium-modified zinc phthalocyanine (Zn-DIGP) that is the first example of a high-affinity G-quadruplex ligand exhibiting both “turn-on” luminescence and the ability to knock-down RNA expression. With a dissociation constant < 2 nM, the interaction between Zn-DIGP and c-Myc G-quadruplex DNA is the highest affinity G-quadruplex – small molecule binding interaction reported to date. Zn-DIGP’s luminescence properties allowed for direct DNA binding assays in vitro and its imaging in vivo. The cellular uptake and localization of Zn-DIGP was different from duplex DNA probes like Hoechst 33342, and at relatively low doses (1 uM) it caused a rapid 3-fold knock-down of c-MYC mRNA in neuroblastoma cells. The exact mechanism responsible for this knock-down is still under investigation, but our results are consistent with quadruplex-mediated promoter deactivation. Taken together, these results indicate that Zn-DIGP is a new tool uniquely suited to help decipher G-quadruplex structure and function.

Abstract

In this manuscript we describe a guanidinium-modified zinc phthalocyanine (Zn-DIGP) that is the first example of a high-affinity G-quadruplex ligand exhibiting both “turn-on” luminescence and the ability to knock-down RNA expression. With a dissociation constant < 2 nM, the interaction between Zn-DIGP and c-Myc G-quadruplex DNA is the highest affinity G-quadruplex – small molecule binding interaction reported to date. Zn-DIGP’s luminescence properties allowed for direct DNA binding assays in vitro and its imaging in vivo. The cellular uptake and localization of Zn-DIGP was different from duplex DNA probes like Hoechst 33342, and at relatively low doses (1 uM) it caused a rapid 3-fold knock-down of c-MYC mRNA in neuroblastoma cells. The exact mechanism responsible for this knock-down is still under investigation, but our results are consistent with quadruplex-mediated promoter deactivation. Taken together, these results indicate that Zn-DIGP is a new tool uniquely suited to help decipher G-quadruplex structure and function.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2009
Deposited On:05 Jan 2010 11:28
Last Modified:16 Dec 2016 11:37
Publisher:Wiley-VCH Verlag
ISSN:1433-7851
Publisher DOI:https://doi.org/10.1002/anie.200903685
PubMed ID:19882707

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