We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton compounds. An exo-cycloadduct prepared from the Diels-Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac 2 O in the presence of a catalytic amount of H 2 SO 4 in order to yield new isoindole derivatives (8a and 8b). The anticancer activity of these compounds was evaluated against MCF-7 (breast adenocarcinoma) and A549 (adenocarcinomic human alveolar basal epithelial) cell lines. The synthesized compounds showed concentration-and time-dependent inhibitory effects on the viability of both cell lines. Compound 8a was more toxic compared to 8b in both cancer cell lines, having higher cytotoxicity against A549 cells. Testing the toxicity properties of these compounds on the BEAS 2B (human bronchial epithelial) cell line indicated that while both compounds decreased the cell viability of cancer cells, they were less toxic on healthy lung cells. Microscopy images of A549 cells after treatment with the new isoindole derivatives displayed characteristic apoptotic morphology compared to BEAS 2B cells. The results demonstrated here suggest that these new compounds might be considered as possible potential anticancer agents for the treatment of lung and breast cancer.
Objective:
Considering this information, firstly, isoindole derivatives containing different functional
groups 4-13 have been synthesized from 2-alkyl/aryl-3a, 4,7,7a-tetrahydro-1H-isoindole-1,
3(2H)-dione.
Background:
Norcantharimides are known as norcantharidine derivatives and contain
an isoindole skeleton structure. Isoindole derivatives have positive effect on inflammatory pathologies
including cancers.
Methods:
For the synthesis of all compounds, 2-alkyl/aryl-3a, 4,7,7a-tetrahydro-1H-isoindole-
1,3(2H)-dione was used as the starting compound. The syntheses were based on two main reactions:
Ene-reaction of singlet oxygen and epoxidation. Secondly, their anticancer activities were
evaluated against HeLa, C6 and A549 cancer cell lines by the BrdU assay.
Results:
Anticancer activities of synthesized compounds (4-13) and 5-FU (5-Florouracil) against
HeLa, C6 and A549 cells were investigated at four concentrations (100, 50, 25 and 5 μM). IC50
values of compounds 4-13 were calculated for all cancer cell lines. The investigated compounds
showed anticancer activity against the cancer cell lines depending on doses. Compound 7 containing
azide and silyl ether exhibited higher inhibitory activity than the other compounds and 5-FU
against A549 cancer cell lines (IC50 =19.41± 0.01 μM). Compounds 9 and 11 were determined to
exhibit cell-selective activity against HeLa cancer cell lines. Compound 11 had higher activity than
the positive control at 100 μM concentrations against C6 cancer cell lines.
Conclusion:
According to the results observed, isoindole derivatives 7, 9, and 11 might be good
potential anticancer agents for the treatment of cervical and glioma cancer due to their antiproliferative
properties, having less cytotoxic effects on healthy cells. In addition, compound 7 could be
used in in vivo studies of all three-cancer cell lines (C6, HeLa, and A549).
New types of norcantharimide analogues were prepared by three methods: epoxidation, photooxidation, and bromination. Epoxidation of deoxynorcantharimide with m-chloroperoxybenzoic acid gave an isomeric mixture. The selective formation of the synisomers was attributed to dipole-dipole interactions between the peracid and imide moiety. Photooxidation of deoxynorcanthamide gave syn-and anti-hydroperoxide analogues through ene addition of singlet oxygen; the anti-hydroperoxide was the major product in this case, as a result of the steric effect of the imide ring. Bromination of deoxynorcantharimide and subsequent transformations gave a pyrrolidine and the phthalimide core structure.
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