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. 2016 Aug 30;6:32213.
doi: 10.1038/srep32213.

Spiro[pyrrolidine-3, 3´-oxindole] as Potent Anti-Breast Cancer Compounds: Their Design, Synthesis, Biological Evaluation and Cellular Target Identification

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Spiro[pyrrolidine-3, 3´-oxindole] as Potent Anti-Breast Cancer Compounds: Their Design, Synthesis, Biological Evaluation and Cellular Target Identification

Santanu Hati et al. Sci Rep. .
Free PMC article

Abstract

The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.

Figures

Figure 1
Figure 1
Representative spiro[pyrrolidine-3, 3´-oxindole] natural and non-natural bioactive compounds, Spirotryptostatin A (1) (inhibits tubulin polymerization), Spirotryptostatin B (2) (inhibits cancer cells at G2/M phase of the cell cycle) and MI-5 (3) (inhibits p53-MDM2 protein-protein interaction).
Figure 2
Figure 2. It depicts a comparison of our one pot strategy against step wise linear sequence of Pictet-Spengler and oxidative ring contraction reaction of tryptamine with appropriate aldehydes.
One of the resulting compounds 5, inhibits proliferation of MCF-7 cells and the putative binding targets are HDAC2 and prohibitin 2.
Figure 3
Figure 3
The new spiro[pyrrolidine-3, 3´-oxindole] scaffold based compounds, 5ao and other analogs were designed by drawing inspiration from natural products such as Chaetocochins G, compound 4 and Vinorelbine.
Figure 4
Figure 4
Synthesis of a library of spiro[pyrrolidine-3, 3´-oxindole] compounds 5bo via one pot Pictet Spengler-oxidative ring contraction of tryptamine at room temperature with variety of aromatic aldehydes were executed.
Figure 5
Figure 5
The retention characteristics of 5l on the nitrocellulose matrix is shown above. HPLC-UV based method indicated 43% of 5l got immobilized on the matrix.
Figure 6
Figure 6
(A) 3D surface representation of HDAC2 is depicted, green color represents the active site residues with which our compound is binding. (B) Stick model represents the binding of 5l with active site residues.

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