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.
Highlights
Breast cancer is one of the most common cause of fatalities in women
We report design of a library of spiro[pyrrolidine-3, 3 ́-oxindole] as potential anti breast cancer molecule that are synthesized via one pot Pictet Spengler-Oxidative ring contraction strategy of tryptamines mediated by N-bromosuccinimide (NBS) (Fig. 2)
Preliminary structure activity relationship (SAR) studies indicated that the aromatic or heteroaromatic functionality on the pyrrole moiety played a crucial role in imparting the inhibitory activity
Summary
Breast cancer is one of the most common cause of fatalities in women. Nearly 12% of the world wide women population is affected by this debilitating disease. For example Spirotryptostatin A and B,1 and 2 inhibits tubulin polymerization and induces cell cycle inhibition of cancer cells at G2/M phase and spirooxindole MI-5, 3, demonstrated novel type of inhibition of p53-MDM2 protein-protein interaction that is critical for modulating tumor suppressing ability of the p53-proteins (Fig. 1)[12,13,14] These interesting therapeutic attributes of spiro[pyrrolidine-3, 3 ́-oxindole] scaffolds, make them attractive synthetic targets. We report design of a library of spiro[pyrrolidine-3, 3 ́-oxindole] as potential anti breast cancer molecule that are synthesized via one pot Pictet Spengler-Oxidative ring contraction strategy of tryptamines mediated by N-bromosuccinimide (NBS) (Fig. 2). Molecular docking of the most active compound in the library with HDAC2 revealed putative binding interaction that could be harnessed to achieve more potent molecules through target based approach
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