Synthesis and evaluation of fused bispyrimidinoacridines as novel pentacyclic analogues of quadruplex-binder BRACO-19.
The present article reports on the design and the synthesis of a series of mono- and bis-pyrimidinoacridines and their evaluation as a novel family of quadruplex-binders. It is shown that bispyrimidinoacridines represent an interesting compromise between easy synthetic access and efficiency in terms of quadruplex interaction (both affinic and selective), as judged by G4-FID assay and molecular modelling. The present study also highlights that control of the pi-stacking interactions taking place between the ligand and the accessible G-tetrad of a quadruplex-DNA is indeed essential for good recognition but not exclusively (key role of direct and water-mediated H-bonds). The introduction of additional amino side chains, valuable in the acridine series, results here in steric perturbations of the ligand/quadruplex recognition and lowers the quadruplex/duplex selectivity.
Debray
Julien
J
Département Chimie Moléculaire, UMR 5250, CNRS/Université Joseph Fourier, BP 53, 38041 Grenoble cedex 9, France.
Zeghida
Walid
W
Jourdan
Muriel
M
Monchaud
David
D
Dheu-Andries
Marie-Louise
ML
Dumy
Pascal
P
Teulade-Fichou
Marie-Paule
MP
Demeunynck
Martine
M
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry; D054856:G-Quadruplexes; D008024:Ligands; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000166:Acridines; D008024:Ligands; D011743:Pyrimidines; C454064:BRACO-19