Rational design of acridine-based ligands with selectivity for human telomeric quadruplexes.
Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.
Sparapani
Silvia
S
CR-UK Biomolecular Structure Group, The School of Pharmacy, University of London, London WC1N 1AX, UK.
Haider
Shozeb M
SM
Doria
Filippo
F
Gunaratnam
Mekala
M
Neidle
Stephen
S
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000737:chemistry / Q000187:drug effects; D014230:Triazoles / Q000737:chemistry
D000166:Acridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D014230:Triazoles; D004247:DNA; C427203:calf thymus DNA; D019009:Proto-Oncogene Proteins c-kit; C509186:TERT protein, human; D019098:Telomerase