DNA interaction and cytotoxicity of a new series of indolo[2,3-b]quinoxaline and pyridopyrazino[2,3-b]indole derivatives. |
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Authors: | P B Arimondo B Baldeyrou W Laine C Bal F A Alphonse S Routier G Coudert J Y Mérour P Colson C Houssier C Bailly |
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Affiliation: | INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Cedex, Lille, France. |
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Abstract: | Absorption, melting temperature and linear dichroism measurements were performed to investigate the interaction with DNA of a series of 16 tricyclic and tetracyclic compounds related to the antiviral agent B-220. The relative DNA affinity of the test compounds containing an indolo[2,3-b]quinoxaline, pyridopyrazino[2,3-b]indoles or pyrazino[2,3-b]indole planar chromophore varies significantly depending on the nature of the side chain grafted onto the indole nitrogen. Compounds with a dimethylaminoethyl chain strongly bind to DNA and exhibit a preference for GC-rich DNA sequences, as revealed by DNase I footprinting. Weaker DNA interactions were detected with those bearing a morpholinoethyl side chain. The incorporation of a 2,3-dihydroxypropyl side chain does not reinforce the DNA interaction compared with the unsubstituted analogues. Both the DNA relaxation assay and cytotoxicity study using two human leukemia cell lines sensitive (HL-60) or resistant (HL-60/MX2) to the antitumor drug mitoxantrone, indicate that topoisomerase II is not a privileged target for the test compounds which only weakly interfere with the catalytic activity of the DNA cleaving enzyme. Cytometry studies showed that the most cytotoxic compounds induce a massive accumulation of cells in the G2/M phase of the cell cycle. Collectively, the data show a relationship between DNA binding and cytotoxicity in the indolo[2,3-b]quinoxaline series. |
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