1. Academic Validation
  2. New Spisulosine Derivative promotes robust autophagic response to cancer cells

New Spisulosine Derivative promotes robust autophagic response to cancer cells

  • Eur J Med Chem. 2020 Feb 15;188:112011. doi: 10.1016/j.ejmech.2019.112011.
Asha Ganesher 1 Priyank Chaturvedi 2 Rohit Sahai 3 Sanjeev Meena 2 Kalyan Mitra 3 Dipak Datta 4 Gautam Panda 5
Affiliations

Affiliations

  • 1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226031, UP, India.
  • 2 Division of Cancer Biology, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226031, UP, India.
  • 3 Electron Microscopy Unit, Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226 031, UP, India.
  • 4 Division of Cancer Biology, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226031, UP, India. Electronic address: dipak.datta@cdri.res.in.
  • 5 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226031, UP, India. Electronic address: gautam.panda@gmail.com.
Abstract

Therapy resistance by evasion of Apoptosis is one of the hallmarks of human Cancer. Therefore, restoration of cell death by non-apoptotic mechanisms is critical to successfully overcome therapy resistance in Cancer. By rational drug design approach, here we try to provide evidence that subtle changes in the chemical structure of spisulosine completely switched its cytotoxic function from Apoptosis to Autophagy. Our most potent molecule (26b) in a series of 16 synthesized derivatives showed robust autophagic cell death in diverse Cancer cells sparing normal counterpart. Compound 26b mediated lethal Autophagy induction was confirmed by formation of characteristic autophagic vacuoles, LC3 puncta formation, upregulation of signature Autophagy markers like Beclin and Atg family proteins. Altogether, we have detected novel Autophagy inducer small molecule which can be tested further for drug discovery research.

Keywords

Autophagy; Chemotherapy; Resistance; Sphingoid; Structure-activity relationship.

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