Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 24, Issue 2, Pages 601-603Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.12.013
Keywords
N-Benzyl indole; Dimethylbarbituric acid; Percentage growth inhibition; Growth inhibitory activity (GI(50)); Lethal concentration (LC50)
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Funding
- NIH/National Cancer Institute [CA140409]
- Arkansas Research Alliance grant
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Based on previous SAR studies on N-benzylindole and barbituric acid hybrid molecules, we have synthesized a series of aromatic substituted 5-((1-benzyl-1H-indol-3-yl) methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs (3a-i) and evaluated them for their in vitro growth inhibition and cytotoxicity against a panel of 60 human tumor cell lines. Compounds 3c, 3d, 3f and 3g were identified as highly potent anti-proliferative compounds against ovarian, renal and breast cancer cell lines with GI(50) values in low the nanomolar range. The 4-methoxy-N-benzyl analog (3d) was the most active compound with GI(50) values of 20 nM and 40 nM against OVCAR-5 ovarian cancer cells and MDA-MB-468 breast cancer cells, respectively. Two other analogs, 3c (the 4-methyl-N-benzyl analog) and 3g (the 4-fluoro-N-benzyl analog) exhibited equimolar potency against MDA-MB-468 cells GI(50) = 30 nM). Analog 3f (the 4-chloro-N-benzyl analog) exhibited a GI(50) value of 40 nM against renal cancer cell line A498. These results suggest that aromatic substituted N-benzylindole dimethylbarbituric acid hybrids may have potential for development as clinical candidates to treat a variety of solid tumors. (C) 2013 Elsevier Ltd. All rights reserved.
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