Targeting telomerase and telomeres: a click chemistry approach towards highly selective G-quadruplex ligands.
Maintenance of telomeres--specialized complexes that protect the ends of chromosomes, is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but is absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types, with little cytotoxic effect outside cancer cells. Here, we describe in detail a new class of G-quadruplex binding ligands synthesized using a click chemistry approach. These ligands comprise a 1,3-di(1,2,3-triazol-4-yl)benzene pharmacophore, and display high levels of selectivity for interaction with G-quadruplex DNA vs. duplex DNA. The ability of these ligands to inhibit the enzymatic activity of telomerase correlates with their ability to stabilize quadruplex DNA, and with estimates of affinity calculated by molecular modeling.
Moorhouse
Adam D
AD
CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK.
Haider
Shozeb
S
Gunaratnam
Mekala
M
Munnur
Deeksha
D
Neidle
Stephen
S
Moses
John E
JE
D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D054856:G-Quadruplexes / Q000187:drug effects*; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C533876:1,3-di(1,2,3-triazol-4-yl)benzene; D001555:Benzene Derivatives; D008024:Ligands; D014230:Triazoles; D004247:DNA; D019098:Telomerase