- Title
- Cytotoxicity of a series of norcantharidin-inspired tetrahydroepoxyisoindole carboxamides
- Creator
- Spare, Lawson K.; Falsetta, Pasquale; Gordon, Christopher P.; Gilbert, Jayne; Harman, David G.; Baker, Mark A.; Li, Feng; McCluskey, Adam; Clegg, Jack K.; Sakoff, Jenette A.; Aldrich-Wright, Janice R.
- Relation
- Chemistry Medicinal Chemistry Vol. 12, Issue 2, p. 130-145
- Publisher Link
- http://dx.doi.org/10.1002/cmdc.201600573
- Publisher
- Wiley-VCH Verlag
- Resource Type
- journal article
- Date
- 2017
- Description
- 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.
- Subject
- antitumor agents; cytotoxicity; intramolecular Diels–Alder; norcantharidin; structure–activity relationships
- Identifier
- http://hdl.handle.net/1959.13/1334274
- Identifier
- uon:27267
- Identifier
- ISSN:1860-7187
- Language
- eng
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