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Cytotoxicity of a Series of Norcantharidin‐Inspired Tetrahydroepoxyisoindole Carboxamides
Author(s) -
Spare Lawson K.,
Falsetta Pasquale,
Gilbert Jayne,
Harman David G.,
Baker Mark A.,
Li Feng,
McCluskey Adam,
Clegg Jack K.,
Sakoff Jennette A.,
AldrichWright Janice R.,
Gordon Christopher P.
Publication year - 2017
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.201600573
Subject(s) - cytotoxicity , stereochemistry , cell culture , chemistry , intramolecular force , cisplatin , cancer research , medicine , in vitro , biochemistry , biology , genetics , chemotherapy
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, (3 S ,3a S ,6 R )‐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, GI 50 =2.9 μ m ) and colon (HT29, GI 50 =6.4 μ m ) cancer cell lines relative to the control (cisplatin), which elicited respective GI 50 values of 6.5 and 11.3 μ m against the aforementioned cell lines. This analogue also displayed improved activity relative to NorC across the breast (MCF‐7, GI 50 =2.9 μ m ; NorC GI 50 =7.5 μ m ), ovarian (A2780, GI 50 =2.2 μ m ; NorC GI 50 =4.4 μ m ), and neuroblastoma (BE2‐C, GI 50 =2.2 μ m ; NorC GI 50 =3.7 μ m ) cancer cell lines. Structure–activity relationship (SAR) investigations demonstrated that retention of sp 2 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.