Synthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene

Stefan B. Lawrenson, Amanda K. Pearce, Sam Hart, Adrian C. Whitwood, Rachel K. O'Reilly, Michael North*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

N-Substituted derivatives of cantharimide and norcantharimide represent a promising but underutilized motif for therapeutic applications. Herein, we report a divergent strategy for the preparation of secondary amides and norcantharimide-resembling spirocyclic imides from a biomass-derived oxanorbornene and assess their biological activity. Computational modelling suggests these compounds fall perfectly within lead-like chemical space (200 Da < RMM < 350 Da, −1 < AlogP < 3), with the spirocyclic imides preferred due to their lack of reactive functionalities. Biological analysis of the spirocyclic imides revealed that the compounds displayed antiproliferative activity against a range of human cancer cells (A549, HCT 116, OVCAR-3, MDA-MB-231, MCF7 and PC-3) with the N-octyl derivative displaying the greatest potential as a potent broad-spectrum anticancer drug. Dose-response curves for the N-octyl spirocyclic imide found EC50 values of 56–95 μM dependent on the cell line, with highest activity against human colorectal carcinoma cells (HCT 116).

Original languageEnglish
Article number131754
JournalTetrahedron
DOIs
Publication statusAccepted/In press - 2020

Bibliographical note

Funding Information:
SL would like to thank the EPSRC (grant number EP/M506680/1 ) and BP plc for financial support. The authors would like to thank the European Research Council for funding (grant number 615142 ).

Publisher Copyright:
© 2020 Elsevier Ltd

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Active surfactants
  • Cantharidin
  • Cytotoxicity
  • Drug design
  • Spirocyclic

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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