Antitumor polycyclic acridines. Part 12. Physical and biological properties of 8,13-diethyl-6-methylquino[4,3,2-kl]acridinium iodide: a lead compound in anticancer drug design.
The biophysical and biological characterization of 8,13-diethyl-6-methylquino[4,3,2-k]lacridinium iodide (6) is reported. The compound binds to DNA, as measured by UV, fluorescence, and circular dichroism studies, and stabilizes the double helix and higher order DNA structures (DNA triplexes and quadruplexes) against thermal denaturation. Unlike many DNA ligands, (6) shows no specificity for binding to specific base pair combinations and does not inhibit topoisomerase I (topo I) or topo II activity. Furthermore, the biological fingerprint elicited by (6) in in vitro evaluations does not compare with clinical agents of the topo II inhibition class. The compound provokes cell cycle arrest in response to DNA damage and the biological sequelae are dependent on the p53 status of the cell line. DNA damage by (6) upregulates p53 and p21(CIP/WAF1) proteins. The unusual structure of (6) and its ease of synthesis in a "one-pot" reaction are features that are being exploited in the design and development of a new series of G-quadruplex stabilizing telomerase inhibitors. However, although the second-generation compounds that resulted from (6) present strong telomerase inhibition, (6) in itself presents yet a different mode of action, with a strong preference for triplex DNA, sequences often found in a number of genes.
Missailidis
Sotiris
S
Cancer Research Laboratories, School of Pharmaceutical Sciences, School of Clinical Laboratory Sciences, University of Nottingham, Nottingham, NG7 2RD, UK. s.missailidis@open.ac.uk
Stanslas
Johnson
J
Modi
Chetna
C
Ellis
Michael J
MJ
Robins
R Adrian
RA
Laughton
Charles A
CA
Stevens
Malcolm F G
MF
D000166:Acridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001671:Biochemistry / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002942:Circular Dichroism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009692:Nucleic Acid Heteroduplexes / Q000187:drug effects / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
C476550:8,13-diethyl-6-methylquino(4,3,2-kl)acridinium iodide; D000166:Acridines; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D009692:Nucleic Acid Heteroduplexes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D004247:DNA