Benzo(h)quinoline derivatives as G-quadruplex binding agents.
G-quadruplexes are unusual structures formed from guanine-rich sequences of nucleic acids. G-quadruplexes have been postulated to play important roles in a number of biological systems including gene regulation and the inhibition of enzyme function. Recently, our laboratory reported on the synthesis and evaluation of a triaza-cyclopentaphenanthrene compound which bound to G-quadruplexes with good affinity and selectivity. This compound contains a 4-pyridone group which has not been previously utilized in other quadruplex binding agents. In this Letter, we describe the synthesis and evaluation of 4-pyridone containing 2- and 3-carboxy-benzoquinolines as G-quadruplex binding agents. We find that these compounds are capable of binding G-quadruplexes with a K(a) in the range of 3 x 10(5)M(-1) and with a 10-fold selectivity for quadruplex over duplex DNA.
Paritala
Hanumantharao
H
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.
Firestine
Steven M
SM
D052160:Benzothiazoles / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004247:DNA / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D005456:Fluorescent Dyes / Q000494:pharmacology; D054856:G-Quadruplexes; D007700:Kinetics; D008956:Models, Chemical; D009696:Nucleic Acids / Q000737:chemistry; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D013696:Temperature
D052160:Benzothiazoles; D002264:Carboxylic Acids; D005456:Fluorescent Dyes; D009696:Nucleic Acids; D011728:Pyridones; D011804:Quinolines; C051000:thiazole orange; C039107:benzo(h)quinoline; C534143:4-pyridone; D004247:DNA