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 language | English |
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Article number | 131754 |
Journal | Tetrahedron |
Volume | 77 |
DOIs | |
Publication status | Accepted/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