title: Design, synthesis, and evaluation of phenanthridine derivatives targeting the telomerase RNA/DNA heteroduplex.
abstract: We are targeting molecules to the RNA/DNA heteroduplex that forms during the enzyme telomerase's catalytic cycle. Telomerase is a potential universal anti-cancer target that we have previously shown can be inhibited by molecules that target this heteroduplex. The aim of this work was to make derivatives of our lead, ethidium, that would allow its straightforward incorporation into molecules in both solid and solution phase. The heteroduplex targeting intercalator will act as a scaffold to allow the incorporation of new functionalities that will interact with specific protein surfaces of telomerase, thereby potentially increasing affinity and specificity. In examining multiple new derivatives of ethidium, with literature precedent or novel, we have identified one, a 5-benzylic acid ethidium derivative that is synthesized in three steps as a single isomer, and completely retains the inhibition efficacy of the parent compound. Furthermore, we have demonstrated that it can be effectively incorporated into resin bound amines on the solid phase. As such it represents an ideal monomer for the exploration of telomerase inhibition or for other applications which would benefit from hybrid molecules that can target duplexes.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA.
authors.forename: Subhashree
authors.initials: S
authors.lastname: Rangarajan
authors.forename: Simon H
authors.initials: SH
authors.lastname: Friedman
mesh_terms: D001665:Binding Sites; D004247:DNA; D015195:Drug Design; D004996:Ethidium; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis; D009692:Nucleic Acid Heteroduplexes / Q000187:drug effects*; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000494:pharmacology; D012313:RNA; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D007364:Intercalating Agents; D009692:Nucleic Acid Heteroduplexes; D010617:Phenanthridines; D012313:RNA; D004247:DNA; D019098:Telomerase; D004996:Ethidium