The effect of pyridyl substituents on the thermodynamics of porphyrin binding to G-quadruplex DNA
详细信息 查看全文
- 作者：Gerald B. Rowl ; Kerry Barnett ; Jesse I. DuPont ; Gopalakrishna Akurathi ; Vu H. Le ; Edwin A. Lewis
- 关键词：G-quadruplex ; DNA ; Ligands ; ITC ; Porphyrins ; Binding
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：1 December, 2013
- 年：2013
- 卷：21
- 期：23
- 页码：7515-7522
- 全文大小：1219 K
文摘
Most of the G-quadruplex interactive molecules reported to date contain extended aromatic flat ring systems and are believed to bind principally by 蟺-蟺 stacking on the end G-tetrads of the quadruplex structure. One such molecule, TMPyP4, (5,10,15,20-tetra(N-methyl-4-pyridyl)porphyrin), exhibits high affinity and some selectivity for G-quadruplex DNA over duplex DNA. Although not a realistic drug candidate, TMPyP4 is used in many nucleic acid research laboratories as a model ligand for the study of small molecule G-quadruplex interactions. Here we report on the synthesis and G-quadruplex interactions of four new cationic porphyrin ligands having only 1, 2, or 3 (N-methyl-4-pyridyl) substituents. The four new ligands are: P(5) (5-(N-methyl-4-pyridyl)porphyrin), P(5,10) (5,10-di(N-methyl-4-pyridyl)porphyrin), P(5,15) (5,15-di(N-methyl-4-pyridyl)porphyrin), and P(5,10,15) (5,10,15-tri(N-methyl-4-pyridyl)porphyrin). Even though these compounds have been previously synthesized, we report alternative synthetic routes that are more efficient and that result in higher yields. We have used ITC, CD, and ESI-MS to explore the effects of the number of N-methyl-4-pyridyl substituents and the substituent position on the porphyrin on the G-quadruplex binding energetics. The relative affinities for binding these ligands to the WT Bcl-2 promoter sequence G-quadruplex are: KTMPyP4 鈮?#xA0;KP(5,15) > KP(5,10,15) >>> KP(5,10), KP(5). The saturation stoichiometry is 2:1 for both P(5,15) and P(5,10,15), while neither P(5) nor P(5,10) exhibit significant complex formation with the WT Bcl-2 promoter sequence G-quadruplex. Additionally, binding of P(5,15) appears to interact by an 鈥榠ntercalation mode鈥?/em> while P(5,10,15) appears to interact by an 鈥榚nd-stacking mode鈥?/em>.