Synthesis of Novel Lipophilic N-Substituted Norcantharimide Derivatives and Evaluation of Their Anticancer Activities

Abstract

This research attempted to study the effect of lipophilicity on the anticancer activity of N-substituted norcantharimide derivatives. Twenty-three compounds were synthesized and their cytotoxicities against five human cancer cell lines studied. The lipophilicity of each derivative was altered by its substituent, an alkyl, alkyloxy, terpenyl or terpenyloxy group at the N-position of norcantharimide. Further, among all synthesized derivatives studied, the compounds N-farnesyloxy-7-oxabicyclo[2.2.1]heptane-2, 3-dicarboximide (9), and N-farnesyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboximide (18), have shown the highest cytotoxicity, anti-proliferative and apoptotic effect against human liver carcinoma HepG2 cell lines, yet displayed no significant cytotoxic effect on normal murine embryonic liver BNL CL.2 cells. Their overall performance led us to believe that these two compounds might be potential candidates for anticancer drugs development.

Insects: an underrepresented resource for the discovery of biologically active natural products

“…Even more impressive neither had significant adverse effects on normal murine embryonic liver cells. Not surprisingly, microscopy of the treated cells showed typical morphological features of apoptosis, such as cell shrinkage, chromatin condensation and DNA fragmentation 123 . The biological activity of norcantharimide analogues with terminal phosphate esters was evaluated against a panel of nine human cancer cell lines: human colon carcinoma cell lines (HT29 and SW480); human breast carcinoma cell line (MCF-7); human ovarian carcinoma cell line (A2780); human lung carcinoma cell line (H460); human skin carcinoma cell line (A431); human prostate carcinoma cell line (DU145); human neuroblastoma cell line (BE2-C); and human glioblastoma cell line (SJ-G2) 125 .…”

“…The lipophilicity of a molecule is an important factor in drug development as it affects solubility and permeability through membranes 124 . Eleven of the molecules showed significant inhibition against all five cancer cell lines tested with a general trend of increased cytotoxicity with increasing side chain length 123 . Thus, the lipophilicity of the N -position of norcantharimide is an important parameter affecting the biological activity of the compound.…”

N-Farnesyloxy-norcantharimide and N-farnesyl-norcantharimide inhibit the progression of leukemia and increase survival days in a syngeneic mouse leukemia model

“…The key starting material in the study was the readily synthesizable 5,6-dehydronorcantharidin, which was prepared on a large scale through exo-selective cycloaddition, or the Diels-Alder reaction, of the relatively cheap furan and maleic anhydride. The details of the manufacturing process can be found in the report by Wu et al [24]. The NOC15 was obtained as a colorless liquid; 1 …”

“…N-Farnesyloxy-norcantharimide (C 23 H 33 NO 4 , designated as NOC15) and N-farnesyl-norcantharimide (C 23 H 33 NO 3 , designated as NC15), which are two newly synthesized NCTD derivatives, have high anticancer activity in cell models [24], but the anticancer effects of NOC15 and NC15 in animal models are not clear yet. Therefore, this study was designed to examine the effects of NOC15 and NC15 on cell viability by using cell cycle analysis and annexin-V apoptosis assay in L1210 cells, and to assess the acute toxicity and anticancer effects of NOC15 and NC15 in a syngeneic mouse model (L1210 cells and DBA/2 mice).…”

Exoconformers ofN-(pyridin-2-yl)- andN-(pyridin-3-yl)norbornene-5,6-dicarboximide crystals

“…N-Octylbicycloheptenedicarboximide (MGK-264) is an active ingre-dient in insect repellents and in some common pesticides (Katz et al, 2008;Hanif & Singh, 2013;Kayedi et al, 2014). Cantharimide derivatives (bicyclic dicarboximides) exhibit anticancer activity, a broad spectrum cytotoxicity, and antiproliferative and antiplasmodial activities (Wu et al, 2014;Hill et al, 2007;Bajsa et al, 2010;Puerto et al, 2013;Robertson et al, 2011). Some norbornenedicarboximides also show binding affinity and selectivity towards serotonin receptors (Fiorino et al, 2014).…”