Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes.

Xiao-Xi Huang,Bin Wu,Yan-Fang Huo,Li-Na Zhu,De-Ming Kong,Na-Na Duan

doi:10.1093/nar/gku526

Abstract

Ligands that can interact specifically with telomeric multimeric G-quadruplexes could be developed as promising anticancer drugs with few side effects related to other G-quadruplex-forming regions. In this paper, a new cationic porphyrin derivative, m-TMPipEOPP, was synthesized and characterized. Its multimeric G-quadruplex recognition specificity under molecular crowding conditions was compared to its isomer p-TMPipEOPP. The slight structural difference accounts for different multimeric G-quadruplex recognition specificity for the two isomers. p-TMPipEOPP can barely discriminate between multimeric and monomeric G-quadruplexes. By contrast, m-TMPipEOPP can bind with multimeric but not with monomeric G-quadruplexes. p-TMPipEOPP might bind to multimeric G-quadruplexes by two modes: sandwich-like end-stacking mode and pocket-dependent intercalative mode. Increasing the pocket size between adjacent two G-quadruplex uints is beneficial for the latter mode. m-TMPipEOPP might bind to multimeric G-quadruplexes by a side binding mode, which confers m-TMPipEOPP with higher multimeric G-quadruplex recognition specificity compared to p-TMPipEOPP. m-TMPipEOPP increases the stability of multimeric G-quadruplex under both dilute and molecular crowding conditions but its G-quadruplex-stabilizing ability is a little weaker than p-TMPipEOPP. These results provide important information for the design of highly specific multimeric G-quadruplex ligands. Another interesting finding is that pocket size is an important factor in determining the stability of multimeric G-quadruplexes.

Highlights

A G-quadruplex is a unique, highly ordered nucleic acid structure formed by guanine (G)-rich deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) [1,2,3]
To investigate the feasibility of using m-TMPipEOPP as a specific G-quadruplex ligand under molecular crowding conditions, binding interactions between m-TMPipEOPP and both monomeric and multimeric G-quadruplexes, duplex or single-stranded DNAs were investigated by following the effects of these DNAs on the UV-vis absorption spectrum of m-TMPipEOPP using polyethylene glycol 200 (PEG 200) as a molecular crowding agent, and the result was compared to p-TMPipEOPP (Figure 1 and Supplementary Figure S4)
A weak absorption peak emerged at ∼666 nm. These results suggest mTMPipEOPP can interact with multimeric G-quadruplexes but not duplex or single-stranded DNAs, implying it might discriminate multimeric G-quadruplexes from duplex and single-stranded DNAs

Summary

Introduction

A G-quadruplex is a unique, highly ordered nucleic acid structure formed by guanine (G)-rich deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) [1,2,3]. Numerous studies have been conducted to investigate the interactions between candidate G-quadruplex ligands and G-quadruplexes formed by telomeric DNAs [18,19,20,21,22,23]. Most of these studies have focused on short telomeric DNA sequences of 20−30 bases [3,24,25,26], which can form only monomeric G-quadruplexes containing a single G-quadruplex unit. Some studies have demonstrated such a Grich single-stranded overhang can fold into G-quadruplexes composed of several G-quadruplex units [27,28,29,30,31,32]. We have reason to believe ligands targeting telomeric multimeric Gquadruplexes are the most promising candidates for anticancer drugs [33,34,35]

Methods

Results

Conclusion