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Chemistry of withaferin-A: chemo, regio, and stereoselective synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A via one-pot three-component [3+2] azomethine ylide cycloaddition and their cytotoxicity evaluation

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Abstract

Withaferin-A (WA) has attracted the attention of chemists as well as biologists due to its interesting structure and various bio-activities. In light of the promising biological importance of WA as well as pyrrolidine-2-spiro-3\(^{\prime }\)-oxindole ring system, we became interested in the synthesis of a combined motif involving both the ring systems via the 1,3-dipolar cycloaddition of WA at \(\Delta ^{2}\)-bond of the \(\upalpha \),\(\upbeta \)-unsaturated carbonyl system. We now report a facile, atom-economic synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A (10 compounds) via the intermolecular cycloaddition of azomethine ylides generated in situ from proline and isatins/acenaphthoquinone. The reaction is highly chemo, regio, and stereoselective affording the cis-fused products with \(\upbeta \)-orienting hydrogen. The structures were determined by 1D/2D NMR spectroscopic data analysis and unequivocally confirmed by X-ray crystallographic analysis in some cases. Bioevaluation of the compounds against six cancer lines (e.g., CHO, HepG2, HeLa, HEK 293, MDCK-II, and Caco-2) identified 4 promising potential anticancer compounds.

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Acknowledgments

The authors express their gratitude to the Director, IICB for laboratory facilities. This work received financial assistance from the Council of Scientific and Industrial Research Government of India. B.Y., S.K., N. S., A.H., and N.B.M. are recipients of Research Fellowships and Emeritus Scientist grant from CSIR. Our thanks are due to Dr. B. Achari (Ex-emeritus Scientist, CSIR) for helpful suggestions and Dr. R. Natarajan (Senior Scientist) and Dr. Prakas R. Maulik (Emeritus Scientist, CSIR) and Mr. Sandip Kundu of IICB for helping in X-ray structure solution and Mr. E. Padmanaban for recording NMR spectrometric data.

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Authors and Affiliations

  1. Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India

    Yogesh P. Bharitkar, Abhijit Hazra & Nirup B. Mondal

  2. National Institute of Pharmaceutical Education and Research, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India

    Satish Kanhar & Neradibilli Suneel

  3. Chembiotek, TCG Lifesciences Ltd, BIPL, Block-EP & GP, Sec-V, Kolkata, 700091, India

    Susanta Kumar Mondal

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  1. Yogesh P. Bharitkar
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Correspondence to Abhijit Hazra or Nirup B. Mondal.

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Bharitkar, Y.P., Kanhar, S., Suneel, N. et al. Chemistry of withaferin-A: chemo, regio, and stereoselective synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A via one-pot three-component [3+2] azomethine ylide cycloaddition and their cytotoxicity evaluation. Mol Divers 19, 251–261 (2015). https://doi.org/10.1007/s11030-015-9574-6

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