title: Antitumor polycyclic acridines. 17. Synthesis and pharmaceutical profiles of pentacyclic acridinium salts designed to destabilize telomeric integrity.
abstract: Palladium(0)-mediated Suzuki-Miyaura and Heck transformations have been exploited to provide examples of 8-methylquino[4,3,2-kl]acridines and 8,13-dimethylquino[4,3,2-kl]acridinium iodides bearing bulky saturated (3-acetoxy)propyl or (E)-3-(morpholin-4-yl)-3-oxopropenyl substituents variously in the 3-, 6-, or 10-positions of the pentacyclic nucleus. The pharmacological/pharmaceutical properties of four compounds (4, RHPS4), (5, IH383), (6, RHPS16), and (17, RHPS19) were measured to assess their clinical potential as DNA G-quadruplex-stabilizing/telomerase inhibitory agents. The following properties were measured: stability in tissue culture media in the presence of A549 lung and MCF-7 breast tumor cells, metabolic stability when incubated with rat liver microsomes, and rate of uptake and subcellular location in A549 and MCF-7 cells. Compound 17 was unstable in tissue culture media, failed to achieve nuclear access, and was excluded from further consideration. Of the other agents, 4 exhibited the most favorable pharmaceutical profile: the agent has appropriate stability in the presence of tumor cells and rat liver microsomes and achieves rapid ingress into cell nuclei where the putative molecular target is located.
authors.affiliation: Cancer Research U.K. Experimental Cancer Chemotherapy Research Group, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Cookson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018613:Microscopy, Confocal; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D003577:Cytochrome P-450 Enzyme System; D019098:Telomerase