Antitumor polycyclic acridines. 8. Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts

被引：109

作者：

Heald, RA

Modi, C

Cookson, JC

Hutchinson, I

Laughton, CA

Gowan, SM

Kelland, LR

Stevens, MFG ^{[1
]}

机构：

[1] Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England

[2] Inst Canc Res, CRC, Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 03期

关键词：

D O I：

10.1021/jm011015q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：590 / 597

页数：8

共 49 条

[1] Telomere states and cell fates [J].