Synthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene

Research output: Contribution to journalArticlepeer-review

Authors

Colleges, School and Institutes

External organisations

  • University of York

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).

Bibliographic 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.

Details

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

Keywords

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