Antitumor Polycyclic Acridines. 20. Search for DNA Quadruplex Binding Selectivity in a Series of 8,13-Dimethylquino[4,3,2-kl]acridinium Salts: Telomere-Targeted Agents

Cheng, Mai-Kim; Modi, Chetna; Cookson, Jennifer C.; Hutchinson, Ian; Heald, Robert A.; McCarroll, Andrew J.; Missailidis, Sotiris; Tanious, Farial; Wilson, W. David; Mergny, Jean-Louis; Laughton, Charles A. and Stevens, Malcolm F. G. (2008). Antitumor Polycyclic Acridines. 20. Search for DNA Quadruplex Binding Selectivity in a Series of 8,13-Dimethylquino[4,3,2-kl]acridinium Salts: Telomere-Targeted Agents. Journal of Medicinal Chemistry, 51(4) pp. 963–975.

DOI: https://doi.org/10.1021/jm070587t

URL: http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/20...

Abstract

The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2-kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R2 = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R2 = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.

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