Cytotoxicity of a series of norcantharidin-inspired tetrahydroepoxyisoindole carboxamides

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.