Cytotoxicity of a Series of Norcantharidin-Inspired Tetrahydroepoxyisoindole Carboxamides

Lawson K Spare; Pasquale Falsetta; Jayne Gilbert; David G Harman; Mark A Baker; Feng Li; Adam McCluskey; Jack K Clegg; Jennette A Sakoff; Janice R Aldrich-Wright; Christopher P Gordon

doi:10.1002/cmdc.201600573

Cytotoxicity of a Series of Norcantharidin-Inspired Tetrahydroepoxyisoindole Carboxamides

ChemMedChem. 2017 Jan 20;12(2):130-145. doi: 10.1002/cmdc.201600573. Epub 2017 Jan 3.

Authors

Lawson K Spare¹, Pasquale Falsetta¹, Jayne Gilbert², David G Harman^{3

4}, Mark A Baker⁵, Feng Li^{1

6}, Adam McCluskey⁷, Jack K Clegg⁸, Jennette A Sakoff², Janice R Aldrich-Wright^{1

6}, Christopher P Gordon^{1

6}

Affiliations

¹ School of Science and Health, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
² Calvary Mater Newcastle, Waratah, NSW, 2298, Australia.
³ School of Medicine, Building 30, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
⁴ Molecular Medicine Research Group, School of Medicine, Building 30, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
⁵ Discipline of Biological Sciences, Priority Research Centre in Reproductive Biology, Faculty of Science and IT, University of Newcastle, Callaghan, NSW, 2308, Australia.
⁶ Nanoscale Organisation and Dynamics Group, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
⁷ Chemistry, School of Environmental and Life Science, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.
⁸ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Street, Lucia, QLD, 4072, Australia.

PMID: 27921386
DOI: 10.1002/cmdc.201600573

Abstract

A series of 28 norcantharidin (NorC)-inspired analogues were accessed via a robust two-step Ugi intramolecular Diels-Alder (IMDA) sequence. Four analogues displayed whole-cell cytotoxicity equipotent to that of NorC and cisplatin against a number of cancer cell lines and a normal breast cell line (MCF10A). Notably, (3S,3aS,6R)-2-benzyl-7-methyl-N-(naphthalen-2-yl)-1-oxo-1,2,3,6-tetrahydro-3a,6-epoxyisoindole-3-carboxamide (trans-27) displayed superior whole-cell activity against breast (MCF-7, GI₅₀ =2.9 μm) and colon (HT29, GI₅₀ =6.4 μm) cancer cell lines relative to the control (cisplatin), which elicited respective GI₅₀ values of 6.5 and 11.3 μm against the aforementioned cell lines. This analogue also displayed improved activity relative to NorC across the breast (MCF-7, GI₅₀ =2.9 μm; NorC GI₅₀ =7.5 μm), ovarian (A2780, GI₅₀ =2.2 μm; NorC GI₅₀ =4.4 μm), and neuroblastoma (BE2-C, GI₅₀ =2.2 μm; NorC GI₅₀ =3.7 μm) cancer cell lines. Structure-activity relationship (SAR) investigations demonstrated that retention of sp² hybridized connections within the tetrahydroepoxyisoindole carboxamide scaffold is crucial, as aromatization to a phenolic functionality decreased activity, whereas removal of a single olefin bond abolished cytotoxicity. Nonetheless, with respect to the latter, use of crotonic acid as opposed 2-butynoic acid in the Ugi-IMDA sequence imparted a significant improvement to diastereoselectivity, with the cis/trans isomer ratio shifting from ≈1:1.2 to ≈0.5:9.5.

Keywords: antitumor agents; cytotoxicity; intramolecular Diels-Alder; norcantharidin; structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemistry*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / toxicity
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Bridged Bicyclo Compounds, Heterocyclic / toxicity
Cell Line, Tumor
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Humans
Isoindoles / chemistry
Isomerism
Molecular Conformation
Structure-Activity Relationship

Substances

Amides
Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
Isoindoles
norcantharidin