Synthesis, cytotoxicity, DNA interaction and topoisomerase II inhibition properties of tetrahydropyrrolo[3,4-a]carbazole-1,3-dione and tetrahydropyrido-[3,2-b]pyrrolo[3,4-g]indole-1,3-dione derivatives. |
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Authors: | B Joseph M Facompré H Da Costa S Routier J Y Mérour P Colson C Houssier C Bailly |
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Institution: | Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'Orléans, BP 6759, 45067 Orléans Cedex 2, France. |
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Abstract: | Three tetrahydropyrrolo3,4-a]carbazole-1,3-diones (6--8) and two tetrahydropyrido3,2-b]pyrrolo3,4-g]indole-1,3-diones (11--12) have been synthesized. Their interaction with DNA was probed by absorption and thermal melting studies. Compounds 8 and 12 both equipped with a hydroxyethyl-aminoethyl side-chain demonstrated higher affinities for poly(dA-dT)(2) than compounds 6, 7 and 11 bearing a dimethylaminoethyl side-chain. Circular and electric linear dichroism measurements showed that all five drugs behave as typical DNA intercalating agents. A plasmid cleavage assay was used to evaluate the capacity of the drugs to inhibit human topoisomerase II. Compounds 8 and 12 which bind strongly to DNA were found to stabilize DNA-topoisomerase II covalent complexes but their topoisomerase II inhibitory properties do not correlate with their cytotoxic potential. Compounds 6 and 7 are essentially inactive whereas compounds 8, 11 and 12 exhibit a high toxicity to P388 murine leukemia cells and provoke a marked accumulation in the G2/M phase of the cell cycle. These compounds form a new class of DNA-targeted antitumor agents. |
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