title: Antitumor polycyclic acridines. 8.(1) Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts.
abstract: Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 microM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, NSC 714186) and a low overall growth-inhibitory activity in the NCI 60 cell panel (mean GI(50) 13.18 microM); in addition, the activity profile of 12d does not COMPARE with agents of the topoisomerase II class. Compound 12d is soluble in water, stable in the pH range of 5-9, efficiently transported into tumor cells, and is currently the lead structure for further elaboration in this new class of telomerase inhibitor.
authors.affiliation: Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.forename: Chetna
authors.initials: C
authors.lastname: Modi
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Cookson
authors.forename: Ian
authors.initials: I
authors.lastname: Hutchinson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Laughton
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Gowan
authors.forename: Lloyd R
authors.initials: LR
authors.lastname: Kelland
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008958:Models, Molecular; D012995:Solubility; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014407:Tumor Cells, Cultured
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D004791:Enzyme Inhibitors; D004247:DNA; D019098:Telomerase