Trisubstituted acridine derivatives as potent and selective telomerase inhibitors.
The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay. The interactions of a number of compounds with a parallel quadruplex DNA structure were simulated by molecular modeling methods. The calculated interaction energies were compared with telomerase activity and showed generally consistent correlations between quadruplex affinity and telomerase inhibition. These data support a model for the action of these compounds that involves the stabilization of intermediate quadruplex structures that inhibit the elongation of telomeric DNA by telomerase in tumor cells.
Harrison
R John
RJ
Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, U.K.
Cuesta
Javier
J
Chessari
Gianni
G
Read
Martin A
MA
Basra
Sanji K
SK
Reszka
Anthony P
AP
Morrell
James
J
Gowan
Sharon M
SM
Incles
Christopher M
CM
Tanious
Farial A
FA
Wilson
W David
WD
Kelland
Lloyd R
LR
Neidle
Stephen
S
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000737:chemistry; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000166:Acridines; D004273:DNA, Neoplasm; D018894:Reverse Transcriptase Inhibitors; D012235:Rhodamines; C022027:lissamine rhodamine B; D004247:DNA; D019098:Telomerase