title: Synthesis and evaluation of analogues of 10H-indolo[3,2-b]quinoline as G-quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase.
abstract: We report here the synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of several rationally-designed quindoline analogues, substituted at the 2- and 7- positions. The ability of these compounds to interact with and stabilise an intramolecular G-quadruplex DNA against increases in temperature was evaluated by a fluorescence-based (FRET) melting assay. The resulting T(m) values were found to correlate with their potency for telomerase inhibition, as measured in an in vitro telomerase TRAP assay. The interactions of a number of compounds with a quadruplex DNA molecular structure were simulated by molecular modelling methods. It is concluded that this class of compound represents a new chemical type suitable for further development as telomerase inhibitors.
authors.affiliation: The School of Chemistry, Queen's University Belfast, Belfast, UK BT9 5AG.
authors.forename: Berangere
authors.initials: B
authors.lastname: Guyen
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schultes
authors.forename: Pascale
authors.initials: P
authors.lastname: Hazel
authors.forename: John
authors.initials: J
authors.lastname: Mann
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D005260:Female; D054856:G-Quadruplexes; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence / Q000379:methods; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D000470:Alkaloids; D026121:Indole Alkaloids; D007211:Indoles; D008024:Ligands; D011804:Quinolines; C024015:cryptolepine; D004247:DNA; D019098:Telomerase