title: Cytotoxicity of a Series of Norcantharidin-Inspired Tetrahydroepoxyisoindole Carboxamides.
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 GI50values 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 sp2hybridized 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.
authors.affiliation: School of Science and Health, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
authors.forename: Lawson K
authors.initials: LK
authors.lastname: Spare
authors.affiliation: School of Science and Health, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Falsetta
authors.affiliation: Calvary Mater Newcastle, Waratah, NSW, 2298, Australia.
authors.forename: Jayne
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: School of Medicine, Building 30, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.|Molecular Medicine Research Group, School of Medicine, Building 30, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Harman
authors.affiliation: Discipline of Biological Sciences, Priority Research Centre in Reproductive Biology, Faculty of Science and IT, University of Newcastle, Callaghan, NSW, 2308, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Baker
authors.affiliation: School of Science and Health, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.|Nanoscale Organisation and Dynamics Group, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Chemistry, School of Environmental and Life Science, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Street, Lucia, QLD, 4072, Australia.
authors.forename: Jack K
authors.initials: JK
authors.lastname: Clegg
authors.affiliation: Calvary Mater Newcastle, Waratah, NSW, 2298, Australia.
authors.forename: Jennette A
authors.initials: JA
authors.lastname: Sakoff
authors.affiliation: School of Science and Health, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.|Nanoscale Organisation and Dynamics Group, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
authors.forename: Janice R
authors.initials: JR
authors.lastname: Aldrich-Wright
authors.affiliation: School of Science and Health, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.|Nanoscale Organisation and Dynamics Group, Western Sydney University, Goldsmith Avenue, Campbelltown, NSW, 2560, Australia.
authors.forename: Christopher P
authors.identifier: 0000-0001-7583-5609
authors.initials: CP
authors.lastname: Gordon
mesh_terms: D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054833:Isoindoles / Q000737:chemistry; D007536:Isomerism; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D054833:Isoindoles; C069741:norcantharidin
keywords: antitumor agents; cytotoxicity; intramolecular Diels-Alder; norcantharidin; structure-activity relationships