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A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton

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Abstract

Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.

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Abbreviations

AKAP9:

A-kinase-anchoring protein 9

DOS:

Diversity-oriented synthesis

MTOC:

Microtubule-organizing centre

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Acknowledgements

Shailja Singh and Subhabrata Sen thank the Department of Biotechnology, Govt. of India, for the pilot grant BT/Med/Pilot Project Cancer/2014. Seema Sehrawat is the recipient of Bio-CARe Award from the Ministry of Science and Technology, Department of Biotechnology, Govt. of India, and acknowledges the funding support. NK and SH are supported by fellowship from Shiv Nadar University. Shailja Singh acknowledges the funding provided by IYBA, Dept. of Biotechnology, Govt. of India. We also sincerely thank financial support received from LRE JNU and ICMR CAR 2016 -17.

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    Authors and Affiliations

    1. Brain Metastasis and NeuroVascular Disease Modeling Lab, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NCR, India

      Naveen Kumar & Seema Sehrawat

    2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 02115, USA

      Seema Sehrawat

    3. Department of Chemistry, School of Natural Sciences, Shiv Nadar University, NH-91, G.B.Nagar, Tehsil Dadri, UP, 201314, India

      Santanu Hati, Parthapratim Munshi & Subhabrata Sen

    4. Host Pathogen Interactions and Disease modeling Group, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NH-91, G.B.Nagar, Tehsil Dadri, UP, 201314, India

      Shailja Singh

    5. Special Centre for Molecular Medicine, JNU, New Delhi, India

      Shailja Singh

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    1. Naveen Kumar
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    Correspondence to Seema Sehrawat or Shailja Singh.

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    Naveen Kumar and Santanu Hati have contributed equally to this work.

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    Kumar, N., Hati, S., Munshi, P. et al. A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton. Mol Cell Biochem 429, 11–21 (2017). https://doi.org/10.1007/s11010-016-2932-6

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    • DOI: https://doi.org/10.1007/s11010-016-2932-6

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