Synthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene. (1st January 2021)

• Record Type: Journal Article
• Authors: Lawrenson, Stefan B.; Pearce, Amanda K.; Hart, Sam; Whitwood, Adrian C.; O'Reilly, Rachel K.; North, Michael
• Is Part Of: Tetrahedron. Volume 77(2021)
• Publication Date: 2021-01-01
• Subjects: Cytotoxicity -- Drug design -- Active surfactants -- Cantharidin -- Spirocyclic; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2020.131754
• Languages: English
• ISSNs: 0040-4020

Abstract

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). Graphical abstract: Image 1