Interaction of a Cationic Porphyrin and Its Metal Derivatives with G-Quadruplex DNA

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• 作者：Eric Boschi ; Supriya Davis ; Scott Taylor ; Andrew Butterworth ; Lilyan A. Chirayath ; Vaishali Purohit ; Laura K. Siegel ; Janesha Buenaventura ; Alexandra H. Sheriff ; Rowen Jin ; Richard Sheardy ; Liliya A. Yatsunyk ; Mahrukh Azam
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：120
• 期：50
• 页码：12807-12819
• 全文大小：614K
• ISSN：1520-5207

文摘

G-quadruplex (GQ) structures formed from guanine-rich sequences are found throughout the genome and are overrepresented in the promoter regions of some oncogenes, at the telomeric ends of eukaryotic chromosomes, and at the 5′-untranslated regions of mRNA. Interaction of small molecule ligands with GQ DNA is an area of great research interest to develop novel anticancer therapeutics and GQ sensors. In this paper we examine the interactions of TMPyP4, its isomer TMPyP2 (containing N-methyl-2-pyridyl substituents, N-Me-2Py) as well as two metal derivatives ZnTMPyP4 and CuTMPyP4 with GQs formed by dT₄G₄ and dT₄G₄T in 100 mM K⁺ or Na⁺ conditions. The DNA sequences were chosen to elucidate the effect of the 3′-T on the stabilization effect of porphyrins, binding modes, affinities, and stoichiometries determined via circular dichroism melting studies, UV–vis titrations, continuous variation analysis, and fluorescence studies. Our findings demonstrate that the stabilizing abilities of porphyrins are stronger toward (dT₄G₄)₄ as compared to (dT₄G₄T)₄ (ΔT_m is 4.4 vs −6.4 for TMPyP4; 12.7 vs 5.7 for TMPyP2; 16.4 vs 12.1 for ZnTMPyP4; and 1.9 vs −8.4 °C for CuTMPyP4) suggesting that the 3′G-tetrad presents at least one of the binding sites. The binding affinity was determined to be moderate (K_a ∼ 10⁶–10⁷ μM^–1) with a typical binding stoichiometry of 1:1 or 2:1 porphyrin-to-GQ. In all studies, ZnTMPyP4 emerged as a ligand superior to TMPyP4. Overall, our work contributes to clearer understanding of interactions between porphyrins and GQ DNA.