6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

doi:10.1186/1756-9966-29-175

Paper

6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

Published Dec 31, 2010 · A. Mukherjee, S. Dutta, M. Shanmugavel

Journal of Experimental & Clinical Cancer Research : CR

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26

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Abstract

BackgroundAnticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl) naphthalimides (compounds 1a-j) were evaluated as antitumor agents.MethodsCompounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied.Results6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC50 value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and transmission electron microscopic studies corroborated its apoptosis inducing efficacy at a concentration of 10 μM in MOLT-4 cells. Its apoptosis induction was also observed in HL-60 cells to an extent much greater than well known apoptosis inducing agents as camptothecin and cis-platin at 10 μM concentration each. It significantly inhibited DNA and RNA synthesis in S-180.ConclusionsIn essence, compound 1i showed potential as an antitumor agent.

In Vitro Study

Study Snapshot

Compound 1i, a potent antitumor agent, induces cell cycle arrest and apoptosis in human tumor cells, with potential for use in clinical trials.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

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Citations

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Hantzsch‐like synthesis of isoquinolino[2,1‐a]quinoline‐12‐carbonitrile incorporating aryl or heteroaryl moieties at C‐13

The Hantzsch-like reaction efficiently synthesized a new series of tetracyclic 13-arylisoquinolino[2,1-a]quinoline12-carbonitrile, with structures confirmed by elemental and spectroscopic data.

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New piperazine derivatives show significant anticancer activity, with the most promising showing a weaker cytotoxic effect on normal cells than cancer cells.

Synthesis and Antitumor Activity of a Series of Novel N-Aryl-5-(2,2,2-trifluoroethoxy)-1,5- dihydro-2H- pyrrol-2-ones Derivatives.

Novel N-Aryl-5-(2,2,2-trifluoroethoxy)-1,5-dihydro-2H-pyrrol-2-one conjugates show moderate to potent anticancer activity against human cancer cell lines, with compounds 2d and 2k showing the most potent effects against acute leukemia

Hantzsch-Like Three-Component Synthesis of 9,10-Dihydro-3H-10a-azaphenanthrene-2,4-dicarbonitriles

This study demonstrates a novel three-component synthesis method for preparing novel 9,10-dihydro-3H-10a-azaphenanthrene-2,4-dicarbonitrile derivatives with bridgehead nitrogens in acetic acid.