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.
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.
Joseph
B
B
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'Orléans, BP 6759, 45067 Orléans Cedex 2, France.
Facompré
M
M
Da Costa
H
H
Routier
S
S
Mérour
J Y
JY
Colson
P
P
Houssier
C
C
Bailly
C
C
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
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