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Eur J Med Chem. 2010 Feb;45(2):705-9. doi: 10.1016/j.ejmech.2009.11.017. Epub 2009 Nov 11.

A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells.

Author information

1
Tumour Biology, Northeastern Ontario Regional Cancer Program at the Sudbury Regional Hospital, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada.

Abstract

The purpose of this study was to evaluate the enhancement value of chloroquine analogs when used in combination with Akt inhibitors on the MDA-MB468, MDA-MB231 and MCF7 human breast cancer cell lines. The result showed that the combination of certain chloroquine analogs and Akt inhibitors are highly effective. In particular, the chloroquine analog N'-(7-fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine (compound 5) was highly effective in sensitizing cancer cell killing when combined with either Akt inhibitor 8 (1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one) or 9 ([4-(2-chloro-4a,10a-dihydro-phenoxazin-10-yl)-butyl]-diethyl-amine hydrochloride). Importantly, the enhancement of chloroquine analogs 5 on cell killing by Akt inhibitors 8 and 9 was cancer-specific. Thus, this combinational approach is highly promising in controlling tumors with a minimum side effect. Structural analysis of effective and ineffective chloroquine analogs suggests that the 4-aminoquinoline scaffold and lateral side chain of dimethylamino functionality play an important role for the enhancement of cell killing by Akt inhibitors.

PMID:
19945197
DOI:
10.1016/j.ejmech.2009.11.017
[Indexed for MEDLINE]

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