title: 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.
abstract: Three tetrahydropyrrolo[3,4-a]carbazole-1,3-diones (6--8) and two tetrahydropyrido[3,2-b]pyrrolo[3,4-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.
authors.affiliation: Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'Orléans, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: B
authors.initials: B
authors.lastname: Joseph
authors.forename: M
authors.initials: M
authors.lastname: Facompré
authors.forename: H
authors.initials: H
authors.lastname: Da Costa
authors.forename: S
authors.initials: S
authors.lastname: Routier
authors.forename: J Y
authors.initials: JY
authors.lastname: Mérour
authors.forename: P
authors.initials: P
authors.lastname: Colson
authors.forename: C
authors.initials: C
authors.lastname: Houssier
authors.forename: C
authors.initials: C
authors.lastname: Bailly
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured
chemical_list: C435817:2-((2-(-hyroxyethyl)amino)ethyl)-10-methyl-1,2,3,10-(2,3-b)pyrrolo(3,4-e)indole-1,3-dione; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors; D004247:DNA