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 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.