کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1364386 | 981535 | 2008 | 6 صفحه PDF | دانلود رایگان |
1-Benzoyl-3-cyanopyrrolo[1,2-a]quinoline (2a) was identified as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 2a had good activity against several breast cancer cell lines but was much less active against several other cancer cell lines. SAR studies of 2a found that substitution at the 4-position of the 1-benzoyl group was important for activity. Replacing the 3-cyano group by an ester or ketone group led to inactive compounds. Interestingly, 4-substituted analogs such as 1-(4-(1H-imidazol-1-yl)benzoyl)-3-cyanopyrrolo[1,2-a]quinoline (2k) were found to be broadly and highly active in the caspase activation assay as well as in the cell growth inhibition assay with low nM EC50 and GI50 values in human breast cancer cells T47D, human colon cancer cells HCT116, and hepatocellular carcinoma cancer cells SNU398. Compound 2a was found not to inhibit tubulin polymerization up to 50 μM, while 2k was found to inhibit tubulin polymerization with an IC50 value of 5 μM, indicating that certain substituents at the 4-position of the 1-benzoyl group can change the mechanism of action.
The discovery and SAR studies of a series of apoptosis inducing 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines with modifications at the 1- and 3-positions is reported.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 18, Issue 23, 1 December 2008, Pages 6259–6264