Synthesis and anti-proliferative activity of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs against human tumor cell lines

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• 作者：Nikhil Reddy Madadi ; Narsimha Reddy Penthala ; Venumadhav Janganati ; Peter A. Crooks
• 关键词：N-Benzyl indole ; Dimethylbarbituric acid ; Percentage growth inhibition ; Growth inhibitory activity (GI50) ; Lethal concentration (LC50)
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 January, 2014
• 年：2014
• 卷：24
• 期：2
• 页码：601-603
• 全文大小：339 K

文摘

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 (ass="boldFont">3a-ass="boldFont">i) and evaluated them for their in vitro growth inhibition and cytotoxicity against a panel of 60 human tumor cell lines. Compounds ass="boldFont">3c, ass="boldFont">3d, ass="boldFont">3f and ass="boldFont">3g were identified as highly potent anti-proliferative compounds against ovarian, renal and breast cancer cell lines with GI₅₀ values in low the nanomolar range. The 4-methoxy-N-benzyl analog (ass="boldFont">3d) was the most active compound with GI₅₀ values of 20 nM and 40 nM against OVCAR-5 ovarian cancer cells and MDA-MB-468 breast cancer cells, respectively. Two other analogs, ass="boldFont">3c (the 4-methyl-N-benzyl analog) and ass="boldFont">3g (the 4-fluoro-N-benzyl analog) exhibited equimolar potency against MDA-MB-468 cells GI₅₀ = 30 nM). Analog ass="boldFont">3f (the 4-chloro-N-benzyl analog) exhibited a GI₅₀ 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.