Synthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene

TY - JOUR

T1 - Synthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene

AU - Lawrenson, Stefan B.

AU - Pearce, Amanda K.

AU - Hart, Sam

AU - Whitwood, Adrian C.

AU - O'Reilly, Rachel K.

AU - North, Michael

N1 - © 2020 Elsevier Ltd. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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).

AB - 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).

KW - Active surfactants

KW - Cantharidin

KW - Cytotoxicity

KW - Drug design

KW - Spirocyclic

UR - http://www.scopus.com/inward/record.url?scp=85097092238&partnerID=8YFLogxK

U2 - 10.1016/j.tet.2020.131754

DO - 10.1016/j.tet.2020.131754

M3 - Article

AN - SCOPUS:85097092238

SN - 0040-4020

VL - 77

JO - Tetrahedron

JF - Tetrahedron

M1 - 131754

ER -