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Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues
Author(s) -
Hizartzidis Lacey,
Gilbert Jayne,
Gordon Christopher P.,
Sakoff Jennette A.,
McCluskey Adam
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900180
Subject(s) - chemistry , cytotoxicity , stereochemistry , heptene , moiety , amide , carboxylic acid , tetrahydroisoquinoline , du145 , bicyclic molecule , biochemistry , biology , prostate , cancer , lncap , in vitro , genetics
Octahydroepoxyisoindole analogues of norcantharidin were accessed through a Diels–Alder reaction of an amine‐substituted furan with maleic anhydride and subsequent reduction of the bicyclo[2.2.1]heptene olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity to norcantharidin, none of these analogues displayed notable cytotoxicity against the 11 cell lines examined: 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 14 acid/amide‐substituted norcantharidin analogues. Of these, only four displayed sufficient activity at the initial 25 μ m compound screening dose to warrant full evaluation of growth inhibition. 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 ( 13 c ) and 3‐(2‐(pyrrole‐2‐ylmethyl)‐3‐(4‐biphenylamino)‐3‐oxopropylcarbamoyl)‐7‐oxabicyclo[2.2.1]heptane‐2‐carboxylic acid ( 24 ) displayed high levels of cytotoxicity, returning GI 50 values of 15 n m (HT29) to 2.9 μ m (U87) and 17 n m (SMA) to 2.8 μ m (U87), respectively. These are the most cytotoxic norcantharidin analogues reported to date.