Synthesis and cytotoxicity of octahydroepoxyisoindole-7-carboxylic acids and norcantharidin-amide hybrids as norcantharidin analogues.

Synthesis and cytotoxicity of octahydroepoxyisoindole-7-carboxylic acids and norcantharidin-amide hybrids as norcantharidin analogues. ChemMedChem. 2019 Apr 01;: Authors: Hizartzidis L, Gilbert J, Gordon CP, Sakoff JA, McCluskey A Abstract Octahydroepoxyisoindole analogues (7a-n) of norcantharidin were accessed through a Diels-Alder reaction of an amine substituted furan with maleic anhydride and subsequent reduction of the bicycle[2.2.1]heptane olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity with norcantharidin, none of these analogues displayed noteworthy cytotoxicity against the 11 cell lines examined herein: HT29 (colon); MCF-7 (breast); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); SJ-G2 and U87 (glioblastoma); MIA (pancreatic); and SMA (spontaneous murine astrocytoma). The incorporation of an amino substituted system post synthesis of norcantharidin afforded facile access to an acid / amide substituted norcantharidin analogues 13-26. Of these only 13c, 24-26 displayed sufficient activity at the initial 25 μM compound screening dose to warrant full growth inhibition evaluation. Common to these analogues was the presence of a 4-biphenyl moiety, and in particular 3-(2-(furan-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid 13c and 3-(2-(pyrrole-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropyl...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research