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Spiro[pyrrolidine-3, 3-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification
Hati S., Tripathy S., Dutta P.K., Agarwal R., Srinivasan R., , Singh S.,
Published in Nature Publishing Group
PMID: 27573798
Volume: 6
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. © The Author(s) 2016.
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Published in Nature Publishing Group
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