Antitumor polycyclic acridines. 8. Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts
Date
2002-01-31ICR Author
Author
Heald, RA
Modi, C
Cookson, JC
Hutchinson, I
Laughton, CA
Gowan, SM
Kelland, LR
Stevens, MFG
Type
Journal Article
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Show full item recordAbstract
Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 muM) 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 muM); 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.
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Language
eng
License start date
2002-01-31
Citation
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 pp. 590 - 597