Antitumor polycyclic acridines. 17. Synthesis and pharmaceutical profiles of pentacyclic acridinium salts designed to destabilize telomeric integrity.
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.
Cookson
Jennifer C
JC
Cancer Research U.K. Experimental Cancer Chemotherapy Research Group, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
Heald
Robert A
RA
Stevens
Malcolm F G
MF
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*
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