Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

Santanu Hati; Sayantan Tripathy; Pratip Kumar Dutta; Rahul Agarwal; Ramprasad Srinivasan; Ashutosh Singh; Shailja Singh; Subhabrata Sen

doi:10.1038/srep32213

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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, Sayantan Tripathy, Pratip Kumar Dutta, Rahul Agarwal, Ramprasad Srinivasan, Ashutosh Singh, Shailja Singh and Subhabrata Sen

Scientific reports, Vol.6(1), pp.32213-32213

08/30/2016

DOI: https://doi.org/10.1038/srep32213

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https://hdl.handle.net/2376/113213

PMCID: PMC5004205

PMID: 27573798

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Abstract

Oxindoles

Apoptosis - drug effects

Antineoplastic Agents - chemical synthesis

Humans

Cercopithecus aethiops

Antineoplastic Agents - chemistry

Pyrrolidines - chemistry

Molecular Dynamics Simulation

Breast Neoplasms - metabolism

Animals

MCF-7 Cells

Breast Neoplasms - pathology

Spiro Compounds - chemical synthesis

Drug Design

Female

Antineoplastic Agents - pharmacology

Cell Proliferation - drug effects

Molecular Structure

COS Cells

Indoles - chemistry

Spiro Compounds - chemistry

Spiro Compounds - pharmacology

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.

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Title: Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification
Creators: Santanu Hati - Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Sayantan Tripathy - Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Pratip Kumar Dutta - Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Rahul Agarwal - Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Ramprasad Srinivasan - Shantani Proteome Analytics Pvt. Ltd. 100 NCL Innovation Park, Dr. HomiBhabha Road, Pune - 411 008, India
Ashutosh Singh - Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Shailja Singh - Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Subhabrata Sen - Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India
Publication Details: Scientific reports, Vol.6(1), pp.32213-32213
Publisher: England
Identifiers: 99900548103501842
Language: English
Resource Type: Journal article